WorldWideScience

Sample records for antitumor immunity induced

  1. Antitumor Immunity Induced after α Irradiation

    Directory of Open Access Journals (Sweden)

    Jean-Baptiste Gorin

    2014-04-01

    Full Text Available Radioimmunotherapy (RIT is a therapeutic modality that allows delivering of ionizing radiation directly to targeted cancer cells. Conventional RIT uses β-emitting radioisotopes, but recently, a growing interest has emerged for the clinical development of α particles. α emitters are ideal for killing isolated or small clusters of tumor cells, thanks to their specific characteristics (high linear energy transfer and short path in the tissue, and their effect is less dependent on dose rate, tissue oxygenation, or cell cycle status than γ and X rays. Several studies have been performed to describe α emitter radiobiology and cell death mechanisms induced after α irradiation. But so far, no investigation has been undertaken to analyze the impact of α particles on the immune system, when several studies have shown that external irradiation, using γ and X rays, can foster an antitumor immune response. Therefore, we decided to evaluate the immunogenicity of murine adenocarcinoma MC-38 after bismuth-213 (213Bi irradiation using a vaccination approach. In vivo studies performed in immunocompetent C57Bl/6 mice induced a protective antitumor response that is mediated by tumor-specific T cells. The molecular mechanisms potentially involved in the activation of adaptative immunity were also investigated by in vitro studies. We observed that 213Bi-treated MC-38 cells release “danger signals” and activate dendritic cells. Our results demonstrate that α irradiation can stimulate adaptive immunity, elicits an efficient antitumor protection, and therefore is an immunogenic cell death inducer, which provides an attractive complement to its direct cytolytic effect on tumor cells.

  2. Intradermal immunization with combined baculovirus and tumor cell lysate induces effective antitumor immunity in mice.

    Science.gov (United States)

    Kawahara, Mamoru; Takaku, Hiroshi

    2013-12-01

    Although tumor lysate contains all the potential helper and killer epitopes capable of stimulating T cells, it is difficult to use as a cancer vaccine because it suppresses dendritic cell (DC) function. We report that wild-type baculovirus possesses an adjuvant effect to improve the immunogenicity of tumor lysate. When mice were administered CT26 tumor cell lysate combined with baculovirus intradermally, antitumor immunity was induced and rejection of CT26 tumor growth was observed in 40% of the immunized mice. In contrast, such antitumor immunity was not elicited in mice inoculated with tumor cell lysate or baculovirus alone. In tumor-bearing mice, which had previously received the combined baculovirus and tumor lysate vaccine, the established tumors were completely eradicated by administering a booster dose of the combined vaccine. This antitumor effect was attributed to tumor-specific T cell immunity mediated primarily by CD8⁺ T cells. Baculovirus also strongly activated DCs loaded with tumor lysate. Increased interleukin (IL)-6 and IL-12p70 production were also observed in DCs co-cultured with tumor cell lysate and baculovirus. Our study demonstrates that combined baculovirus and tumor lysate vaccine can effectively stimulate DCs to induce acquired antitumor immunity.

  3. Nanovectorized radiotherapy: a new strategy to induce anti-tumor immunity

    International Nuclear Information System (INIS)

    Vanpouille-Box, Claire; Hindré, François

    2012-01-01

    Recent experimental findings show that activation of the host immune system is required for the success of chemo- and radiotherapy. However, clinically apparent tumors have already developed multiple mechanisms to escape anti-tumor immunity. The fact that tumors are able to induce a state of tolerance and immunosuppression is a major obstacle in immunotherapy. Hence, there is an overwhelming need to develop new strategies that overcome this state of immune tolerance and induce an anti-tumor immune response both at primary and metastatic sites. Nanovectorized radiotherapy that combines ionizing radiation and nanodevices, is one strategy that could boost the quality and magnitude of an immune response in a predictable and designable fashion. The potential benefits of this emerging treatment may be based on the unique combination of immunostimulatory properties of nanoparticles with the ability of ionizing radiation to induce immunogenic tumor cell death. In this review, we will discuss available data and propose that the nanovectorized radiotherapy could be a powerful new strategy to induce anti-tumor immunity required for positive patient outcome.

  4. Nanovectorized radiotherapy, a new strategy to induce anti-tumor immunity

    Directory of Open Access Journals (Sweden)

    Claire eVanpouille-Box

    2012-10-01

    Full Text Available Recent experimental findings show that activation of the host immune system is required for the success of chemo- and radio-therapy. However, clinically-apparent tumors have already developed multiple mechanisms to escape anti-tumor immunity. The fact that tumors are able to induce a state of tolerance and immunosuppression is a major obstacle in immunotherapy. Hence, there is an overwhelming need to develop new strategies that overcome this state of immune tolerance and induce an anti-tumor immune response both at primary and metastatic sites. Nanovectorized radiotherapy that combines ionizing radiation and nano-devices, is one strategy that could boost the quality and magnitude of an immune response in a predictable and designable fashion. The potential benefits of this emerging treatment may be based on the unique combination of immuno-stimulatory properties of nanoparticles with the ability of ionizing radiation to induce immunogenic tumor cell death. In this review, we will discuss available data and propose that the nanovectorized radiotherapy could be a powerful new strategy to induce anti-tumor immunity required for positive patient outcome.

  5. Investigation of HIFU-induced anti-tumor immunity in a murine tumor model

    Directory of Open Access Journals (Sweden)

    Lyerly H Kim

    2007-07-01

    Full Text Available Abstract Background High intensity focused ultrasound (HIFU is an emerging non-invasive treatment modality for localized treatment of cancers. While current clinical strategies employ HIFU exclusively for thermal ablation of the target sites, biological responses associated with both thermal and mechanical damage from focused ultrasound have not been thoroughly investigated. In particular, endogenous danger signals from HIFU-damaged tumor cells may trigger the activation of dendritic cells. This response may play a critical role in a HIFU-elicited anti-tumor immune response which can be harnessed for more effective treatment. Methods Mice bearing MC-38 colon adenocarcinoma tumors were treated with thermal and mechanical HIFU exposure settings in order to independently observe HIFU-induced effects on the host's immunological response. In vivo dendritic cell activity was assessed along with the host's response to challenge tumor growth. Results Thermal and mechanical HIFU were found to increase CD11c+ cells 3.1-fold and 4-fold, respectively, as compared to 1.5-fold observed for DC injection alone. In addition, thermal and mechanical HIFU increased CFSE+ DC accumulation in draining lymph nodes 5-fold and 10-fold, respectively. Moreover, focused ultrasound treatments not only caused a reduction in the growth of primary tumors, with tumor volume decreasing by 85% for thermal HIFU and 43% for mechanical HIFU, but they also provided protection against subcutaneous tumor re-challenge. Further immunological assays confirmed an enhanced CTL activity and increased tumor-specific IFN-γ-secreting cells in the mice treated by focused ultrasound, with cytotoxicity induced by mechanical HIFU reaching as high as 27% at a 10:1 effector:target ratio. Conclusion These studies present initial encouraging results confirming that focused ultrasound treatment can elicit a systemic anti-tumor immune response, and they suggest that this immunity is closely related to

  6. Inducing Optimal Antitumor Immune Response through Coadministering iRGD with Pirarubicin Loaded Nanostructured Lipid Carriers for Breast Cancer Therapy.

    Science.gov (United States)

    Deng, Caifeng; Jia, Mengdi; Wei, Guangfei; Tan, Tiantian; Fu, Yao; Gao, Huile; Sun, Xun; Zhang, Quan; Gong, Tao; Zhang, Zhirong

    2017-01-03

    Chemotherapeutic agents trigger antitumor immune response through inducing immunogenic tumor cell death. However, severe toxicity to immune system and insufficient immunogenic cell death hinder chemotherapy from arousing efficient antitumor immunity in vivo. In this study, the cytotoxic drug, pirarubicin (THP), was entrapped into nanostructured lipid carriers (NLC); THP-NLC significantly reduced the toxicity of THP to immune system and improved immune status of breast cancer bearing mice. When THP-NLC was coinjected with iRGD (a tumor-penetrating peptide), drug accumulation in tumors was greatly elevated, which led to significant control of tumor growth and increase of immunogenic tumor cell death. Subsequently, the cytotoxic T lymphocytes (CD3 + and CD8 + cells) infiltration and cytokine (IFN-γ and INF-α) secretion in tumors were heavily increased. The efficient T-cell dependent control of tumors in the late stage and the lower side effects contributed to the longest whole survival of THP-NLC + iRGD treated mice. Therefore, the coadministration of THP-NLC with iRGD resulted in increased tumor cell direct-killing death and enhanced antitumor immune response. Our results illustrated that THP could serve as an immunogenic cell death inducer and the proposed drug delivery strategy might impact cancer immunotherapy by arousing increased immunogenic tumor cell death.

  7. Passive adoptive transfer of antitumor immunity induced by laser-dye-immunoadjuvant treatment in a rat metastatic breast cancer model

    Science.gov (United States)

    Chen, Wei R.; Liu, Hong; Singhal, Anil K.; Nordquist, Robert E.

    2000-06-01

    The ideal cancer treatment modalities should not only cause tumor regression and eradication but also induce a systemic anti-tumor immunity. This is essential for control of metastatic tumors and for long-term tumor resistance. Laser immunotherapy using a laser, a laser-absorbing dye and an immunoadjuvant has induced such a long-term immunity in treatment of a mammary metastatic tumor. The successfully treated rats established total resistance to multiple subsequent tumor challenges. For further mechanistic studies of the antitumor immunity induced by this novel treatment modality, passive adoptive transfer was performed using splenocytes as immune cells. The spleen cells harvested from successfully treated tumor-bearing rats provided 100% immunity in the naive recipients. The passively protected first cohort rats were immune to tumor challenge with an increased tumor dose; their splenocytes also prevented the establishment of tumor in the second cohort of naive recipient rats. This immunity transfer was accomplished without the usually required T-cell suppression in recipients.

  8. A novel, polymer-coated oncolytic measles virus overcomes immune suppression and induces robust antitumor activity

    Directory of Open Access Journals (Sweden)

    Kaname Nosaki

    2016-01-01

    Full Text Available Although various therapies are available to treat cancers, including surgery, chemotherapy, and radiotherapy, cancer has been the leading cause of death in Japan for the last 30 years, and new therapeutic modalities are urgently needed. As a new modality, there has recently been great interest in oncolytic virotherapy, with measles virus being a candidate virus expected to show strong antitumor effects. The efficacy of virotherapy, however, was strongly limited by the host immune response in previous clinical trials. To enhance and prolong the antitumor activity of virotherapy, we combined the use of two newly developed tools: the genetically engineered measles virus (MV-NPL and the multilayer virus-coating method of layer-by-layer deposition of ionic polymers. We compared the oncolytic effects of this polymer-coated MV-NPL with the naked MV-NPL, both in vitro and in vivo. In the presence of anti-MV neutralizing antibodies, the polymer-coated virus showed more enhanced oncolytic activity than did the naked MV-NPL in vitro. We also examined antitumor activities in virus-treated mice. Complement-dependent cytotoxicity and antitumor activities were higher in mice treated with polymer-coated MV-NPL than in mice treated with the naked virus. This novel, polymer-coated MV-NPL is promising for clinical cancer therapy in the future.

  9. Cryo-thermal therapy elicits potent anti-tumor immunity by inducing extracellular Hsp70-dependent MDSC differentiation

    Science.gov (United States)

    Zhu, Jun; Zhang, Yan; Zhang, Aili; He, Kun; Liu, Ping; Xu, Lisa X.

    2016-01-01

    Achieving control of metastatic disease is a long-sought goal in cancer therapy. Treatments that encourage a patient’s own immune system are bringing new hopes in reaching such a goal. In clinic, local hyperthermia and cryoablation have been explored to induce anti-tumor immune responses against tumors. We have also developed a novel therapeutic modality of cryo-thermal treatment by alternating liquid nitrogen (LN2) cooling and radio frequency (RF) heating, and better therapeutic effect was achieved in treating metastatic cancer in animal model. In this study, we investigated the mechanism of systemic immune response elicited by cryo-thermal therapy. In the 4T1 murine mammary carcinoma model, we found that local cryo-thermal therapy resulted in a considerable reduction of distant lung metastases, and improved long-term survival. Moreover, results of tumor re-challenge experiments indicated generation of a strong tumor-specific immune memory after the local treatment of primary tumors. Our further study indicated that cryo-thermal therapy caused an elevated extracellular release of Hsp70. Subsequently, Hsp70 induced differentiation of MDSCs into mature DCs, contributing to the relief of MDSCs-mediated immunosuppression and ultimately the activation of strong anti-tumor immune response. Our findings reveal new insight into the mechanism of robust therapeutic effects of cryo-thermal therapy against metastatic cancers. PMID:27256519

  10. Fractional laser exposure induces neutrophil infiltration (N1 phenotype into the tumor and stimulates systemic anti-tumor immune response.

    Directory of Open Access Journals (Sweden)

    Masayoshi Kawakubo

    Full Text Available Ablative fractional photothermolysis (aFP using a CO2 laser generates multiple small diameter tissue lesions within the irradiation field. aFP is commonly used for a wide variety of dermatological indications, including treatment of photodamaged skin and dyschromia, drug delivery and modification of scars due to acne, surgical procedures and burns. In this study we explore the utility of aFP for treating oncological indications, including induction of local tumor regression and inducing anti-tumor immunity, which is in marked contrast to current indications of aFP.We used a fractional CO2 laser to treat a tumor established by BALB/c colon carcinoma cell line (CT26.CL25, which expressed a tumor antigen, beta-galactosidase (beta-gal. aFP treated tumors grew significantly slower as compared to untreated controls. Complete remission after a single aFP treatment was observed in 47% of the mice. All survival mice from the tumor inoculation rejected re-inoculation of the CT26.CL25 colon carcinoma cells and moreover 80% of the survival mice rejected CT26 wild type colon carcinoma cells, which are parental cells of CT26.CL25 cells. Histologic section of the FP-treated tumors showed infiltrating neutrophil in the tumor early after aFP treatment. Flow cytometric analysis of tumor-infiltrating lymphocytes showed aFP treatment abrogated the increase in regulatory T lymphocyte (Treg, which suppresses anti-tumor immunity and elicited the expansion of epitope-specific CD8+ T lymphocytes, which were required to mediate the tumor-suppressing effect of aFP.We have demonstrated that aFP is able to induce a systemic anti-tumor adaptive immunity preventing tumor recurrence in a murine colon carcinoma in a mouse model. This study demonstrates a potential role of aFP treatments in oncology and further studies should be performed.

  11. The mannosylated extracellular domain of Her2/neu produced in P. pastoris induces protective antitumor immunity

    International Nuclear Information System (INIS)

    Dimitriadis, Alexios; Gontinou, Chrysanthi; Baxevanis, Constantin N; Mamalaki, Avgi

    2009-01-01

    Her2/neu is overexpressed in various human cancers of epithelial origin and is associated with increased metastatic potential and poor prognosis. Several attempts have been made using the extracellular domain of Her2/neu (ECD/Her2) as a prophylactic vaccine in mice with no success in tumor prevention. The extracellular domain of Her2/neu (ECD/Her2) was expressed in yeast P. pastoris, in a soluble highly mannosylated form. The immune response of the immunization with this recombinant ECD/Her2 was analyzed using immunoprecipitation and western blot analysis, proliferation and cytotoxicity assays as well as specific tumor growth assays. Mannosylated ECD/Her2 elicited a humoral response with HER2/neu specific antibodies in vaccinated mice, which were able to reduce the proliferation rate of cancer cells in vitro. Moreover, it elicited a cellular response with Her2/neu-specific CTL capable of lysing tumor cells, in vitro. When immunized Balb/c and HHD mice were challenged with Her2/neu-overexpressing cells, tumor growth was inhibited. Here we report on the efficacy of the extracellular domain of human Her2/neu produced in yeast P. pastoris, which confers mannosylation of the protein, to act as a potent anti-tumor vaccine against Her2/neu overexpressing tumors. Specific cellular and humoral responses were observed as well as efficacy

  12. Immune response to uv-induced tumors: transplantation immunity and lymphocyte populations exhibiting anti-tumor activity

    International Nuclear Information System (INIS)

    Streeter, P.R.

    1985-01-01

    Ultraviolet light-induced murine skin tumors were analyzed for their ability to induce tumor-specific and cross-protective transplantation immunity in immunocompetent syngeneic mice. These studies revealed that progressor UV-tumors, like regressor UV-tumors, possess tumor-specific transplantation antigens. Cross-protective transplantation immunity to UV-tumors, however, was associated with sensitization to the serum used to culture the tumor lines rather than to cross-reactive or common determinants on UV-tumors. An analysis of the cytolytic activity of lymphocytes from the spleens of mice immunized with either regressor or progressor UV-tumors revealed a striking difference between the two immune splenocyte populations. From regressor tumor-immune animals, cytolytic T (Tc) lymphocytes with specificity for the immunizing tumor were found. However, the analysis of splenic lymphocytes from progressor tumor immune animals revealed no such effector cells. To more effectively examine those lymphocytes exhibiting cytolytic activity in vitro, T lymphocyte cloning technology was used as a means of isolating homogeneous lymphocyte populations with the effector activities described above. The mechanisms where NK cells and other nonspecific effector cells could be induced in tumor-immune animals are discussed in the context of class II restricted immune responses

  13. Vaccination with Necroptotic Cancer Cells Induces Efficient Anti-tumor Immunity

    Directory of Open Access Journals (Sweden)

    Tania Løve Aaes

    2016-04-01

    Full Text Available Successful immunogenic apoptosis in experimental cancer therapy depends on the induction of strong host anti-tumor responses. Given that tumors are often resistant to apoptosis, it is important to identify alternative molecular mechanisms that elicit immunogenic cell death. We have developed a genetic model in which direct dimerization of FADD combined with inducible expression of RIPK3 promotes necroptosis. We report that necroptotic cancer cells release damage-associated molecular patterns and promote maturation of dendritic cells, the cross-priming of cytotoxic T cells, and the production of IFN-γ in response to tumor antigen stimulation. Using both FADD-dependent and FADD-independent RIPK3 induction systems, we demonstrate the efficient vaccination potential of immunogenic necroptotic cells. Our study broadens the current concept of immunogenic cell death and opens doors for the development of new strategies in cancer therapy.

  14. Trypanosoma cruzi Adjuvants Potentiate T Cell-Mediated Immunity Induced by a NY-ESO-1 Based Antitumor Vaccine

    Science.gov (United States)

    Junqueira, Caroline; Guerrero, Ana Tereza; Galvão-Filho, Bruno; Andrade, Warrison A.; Salgado, Ana Paula C.; Cunha, Thiago M.; Ropert, Catherine; Campos, Marco Antônio; Penido, Marcus L. O.; Mendonça-Previato, Lúcia; Previato, José Oswaldo; Ritter, Gerd; Cunha, Fernando Q.; Gazzinelli, Ricardo T.

    2012-01-01

    Immunological adjuvants that induce T cell-mediate immunity (TCMI) with the least side effects are needed for the development of human vaccines. Glycoinositolphospholipids (GIPL) and CpGs oligodeoxynucleotides (CpG ODNs) derived from the protozoa parasite Trypanosoma cruzi induce potent pro-inflammatory reaction through activation of Toll-Like Receptor (TLR)4 and TLR9, respectively. Here, using mouse models, we tested the T. cruzi derived TLR agonists as immunological adjuvants in an antitumor vaccine. For comparison, we used well-established TLR agonists, such as the bacterial derived monophosphoryl lipid A (MPL), lipopeptide (Pam3Cys), and CpG ODN. All tested TLR agonists were comparable to induce antibody responses, whereas significant differences were noticed in their ability to elicit CD4+ T and CD8+ T cell responses. In particular, both GIPLs (GTH, and GY) and CpG ODNs (B344, B297 and B128) derived from T. cruzi elicited interferon-gamma (IFN-γ) production by CD4+ T cells. On the other hand, the parasite derived CpG ODNs, but not GIPLs, elicited a potent IFN-γ response by CD8+ T lymphocytes. The side effects were also evaluated by local pain (hypernociception). The intensity of hypernociception induced by vaccination was alleviated by administration of an analgesic drug without affecting protective immunity. Finally, the level of protective immunity against the NY-ESO-1 expressing melanoma was associated with the magnitude of both CD4+ T and CD8+ T cell responses elicited by a specific immunological adjuvant. PMID:22567144

  15. Hapten-Induced Contact Hypersensitivity, Autoimmune Reactions, and Tumor Regression: Plausibility of Mediating Antitumor Immunity

    Directory of Open Access Journals (Sweden)

    Dan A. Erkes

    2014-01-01

    Full Text Available Haptens are small molecule irritants that bind to proteins and elicit an immune response. Haptens have been commonly used to study allergic contact dermatitis (ACD using animal contact hypersensitivity (CHS models. However, extensive research into contact hypersensitivity has offered a confusing and intriguing mechanism of allergic reactions occurring in the skin. The abilities of haptens to induce such reactions have been frequently utilized to study the mechanisms of inflammatory bowel disease (IBD to induce autoimmune-like responses such as autoimmune hemolytic anemia and to elicit viral wart and tumor regression. Hapten-induced tumor regression has been studied since the mid-1900s and relies on four major concepts: (1 ex vivo haptenation, (2 in situ haptenation, (3 epifocal hapten application, and (4 antigen-hapten conjugate injection. Each of these approaches elicits unique responses in mice and humans. The present review attempts to provide a critical appraisal of the hapten-mediated tumor treatments and offers insights for future development of the field.

  16. Transgenic expression of soluble human CD5 enhances experimentally-induced autoimmune and anti-tumoral immune responses.

    Directory of Open Access Journals (Sweden)

    Rafael Fenutría

    Full Text Available CD5 is a lymphoid-specific transmembrane glycoprotein constitutively expressed on thymocytes and mature T and B1a lymphocytes. Current data support the view that CD5 is a negative regulator of antigen-specific receptor-mediated signaling in these cells, and that this would likely be achieved through interaction with CD5 ligand/s (CD5L of still undefined nature expressed on immune or accessory cells. To determine the functional consequence of loss of CD5/CD5L interaction in vivo, a new transgenic mouse line was generated (shCD5EμTg, expressing a circulating soluble form of human CD5 (shCD5 as a decoy to impair membrane-bound CD5 function. These shCD5EμTg mice showed an enhanced response to autologous antigens, as deduced from the presentation of more severe forms of experimentally inducible autoimmune disease (collagen-induced arthritis, CIA; and experimental autoimmune encephalitis, EAE, as well as an increased anti-tumoral response in non-orthotopic cancer models (B16 melanoma. This enhancement of the immune response was in agreement with the finding of significantly reduced proportions of spleen and lymph node Treg cells (CD4+CD25+FoxP3+, and of peritoneal IL-10-producing and CD5+ B cells, as well as an increased proportion of spleen NKT cells in shCD5EμTg mice. Similar changes in lymphocyte subpopulations were observed in wild-type mice following repeated administration of exogenous recombinant shCD5 protein. These data reveal the relevant role played by CD5/CD5L interactions on the homeostasis of some functionally relevant lymphocyte subpopulations and the modulation of immune responses to autologous antigens.

  17. Dendritic cells loaded with pancreatic Cancer Stem Cells (CSCs lysates induce antitumor immune killing effect in vitro.

    Directory of Open Access Journals (Sweden)

    Tao Yin

    Full Text Available According to the cancer stem cells (CSCs theory, malignant tumors may be heterogeneous in which a small population of CSCs drive the progression of cancer. Because of their intrinsic abilities, CSCs may survive a variety of treatments and then lead to therapeutic resistance and cancer recurrence. Pancreatic CSCs have been reported to be responsible for the malignant behaviors of pancreatic cancer, including suppression of immune protection. Thus, development of immune strategies to eradicate pancreatic CSCs may be of great value for the treatment of pancreatic cancer. In this study, we enriched pancreatic CSCs by culturing Panc-1 cells under sphere-forming conditions. Panc-1 CSCs expressed low levels of HLA-ABC and CD86, as measured by flow cytometry analysis. We further found that the Panc-1 CSCs modulate immunity by inhibiting lymphocyte proliferation which is promoted by phytohemagglutinin (PHA and anti-CD3 monoclonal antibodies. The monocyte derived dendritic cells (DCs were charged with total lysates generated from Panc-1 CSCs obtained from tumor sphere culturing. After co-culturing with lymphocytes at different ratios, the Panc-1 CSCs lysates modified DC effectively promoted lymphocyte proliferation. The activating efficiency reached 72.4% and 74.7% at the ratios of 1∶10 and 1∶20 with lymphocytes. The activated lymphocytes secreted high levels of INF-γ and IL-2, which are strong antitumor cytokines. Moreover, Panc-1 CSCs lysates modified DC induced significant cytotoxic effects of lymphocytes on Panc-1 CSCs and parental Panc-1 cells, respectively, as shown by lactate dehydrogenase (LDH assay. Our study demonstrates that the development of CSCs-based vaccine is a promising strategy for treating pancreatic cancer.

  18. A whole-cell tumor vaccine modified to express fibroblast activation protein induces antitumor immunity against both tumor cells and cancer-associated fibroblasts.

    Science.gov (United States)

    Chen, Meihua; Xiang, Rong; Wen, Yuan; Xu, Guangchao; Wang, Chunting; Luo, Shuntao; Yin, Tao; Wei, Xiawei; Shao, Bin; Liu, Ning; Guo, Fuchun; Li, Meng; Zhang, Shuang; Li, Minmin; Ren, Kexing; Wang, Yongsheng; Wei, Yuquan

    2015-09-23

    Cancer-associated fibroblasts (CAFs) are common components of the tumor-suppressive microenvironment, and are a major determinant of the poor outcome of therapeutic vaccination. In this study, we modified tumor cells to express the fibroblast activation protein (FAP), which is highly expressed by CAFs, to potentially improve whole-cell tumor vaccines by targeting both tumor cells and CAFs. Tumor cells were transfected with murine FAP plasmids bearing the cationic lipid DOTAP. Its antitumor effects were investigated in three established tumor models. Vaccination with tumor cells expressing FAP eliminated solid tumors and tumors resulting from hematogenous dissemination. This antitumor immune response was mediated by CD8+ T cells. Additionally, we found that CAFs were significantly reduced within the tumors. Furthermore, this vaccine enhanced the infiltration of CD8+ T lymphocytes, and suppressed the accumulation of immunosuppressive cells in the tumor microenvironment. Our results indicated that the FAP-modified whole-cell tumor vaccine induced strong antitumor immunity against both tumor cells and CAFs and reversed the immunosuppressive effects of tumors by decreasing the recruitment of immunosuppressive cells and enhancing the recruitment of effector T cells. This conclusion may have important implications for the clinical use of genetically modified tumor cells as cancer vaccines.

  19. CCL3 and CCL20-recruited dendritic cells modified by melanoma antigen gene-1 induce anti-tumor immunity against gastric cancer ex vivo and in vivo.

    Science.gov (United States)

    He, Songbing; Wang, Liang; Wu, Yugang; Li, Dechun; Zhang, Yanyun

    2010-04-27

    To investigate whether dendritic cell (DC) precursors, recruited by injection of chemokine ligand 3 (CCL3) and CCL20, induce anti-tumor immunity against gastric cancer induced by a DC vaccine expressing melanoma antigen gene-1 (MAGE-1) ex vivo and in vivo. B6 mice were injected with CCL3 and CCL20 via the tail vein. Freshly isolated F4/80-B220-CD11c+ cells cultured with cytokines were analyzed by phenotype analysis and mixed lymphocyte reaction (MLR). For adenoviral (Ad)-mediated gene transduction, cultured F4/80-B220-CD11c+ cells were incubated with Ad-MAGE-1. Vaccination of stimulated DC induced T lymphocytes. The killing effect of these T cells against gastric carcinoma cells was assayed by MTT. INF-gamma production was determined with an INF-gamma ELISA kit. In the solid tumor and metastases model, DC-based vaccines were used for immunization after challenge with MFC cells. Tumor size, survival of mice, and number of pulmonary metastatic foci were used to assess the therapeutic effect of DC vaccines. F4/80-B220-CD11c+ cell numbers increased after CCL3 and CCL20 injection. Freshly isolated F4/80-B220-CD11c+ cells cultured with cytokines were phenotyically identical to typical DC and gained the capacity to stimulate allogeneic T cells. These DCs were transduced with Ad-MAGE-1, which were prepared for DC vaccines expressing tumor antigen. T lymphocytes stimulated by DCs transduced with Ad-MAGE-1 exhibited specific killing effects on gastric carcinoma cells and produced high levels of INF-gamma ex vivo. In vivo, tumor sizes of the experimental group were much smaller than both the positive control group and the negative control groups (P anti-tumor immunity specific to gastric cancer ex vivo and in vivo. This system may prove to be an efficient strategy for anti-tumor immunotherapy.

  20. Human papillomavirus type 16 E6-specific antitumor immunity is induced by oral administration of HPV16 E6-expressing Lactobacillus casei in C57BL/6 mice.

    Science.gov (United States)

    Lee, Tae-Young; Kim, Yang-Hyun; Lee, Kyung-Soon; Kim, Jeong-Ki; Lee, Il-Han; Yang, Jai-Myung; Sung, Moon-Hee; Park, Jong-Sup; Poo, Haryoung

    2010-11-01

    Given that local cell-mediated immunity (CMI) against the human papillomavirus type 16 E6 (HPV16 E6) protein is important for eradication of HPV16 E6-expressing cancer cells in the cervical mucosa, the HPV16 E6 protein may be a target for the mucosal immunotherapy of cervical cancer. Here, we expressed the HPV16 E6 antigen on Lactobacillus casei (L. casei) and investigated E6-specific CMI following oral administration of the L. casei-PgsA-E6 to mice. Surface expression of HPV16 E6 antigens was confirmed and mice were orally inoculated with the L. casei-PgsA or the L. casei-PgsA-E6. Compared to the L. casei-PgsA-treated mice, significantly higher levels of serum IgG and mucosal IgA were observed in L. casei-PgsA-E6-immunized mice; these differences were significantly enhanced after boost. Consistent with this, systemic and local CMI were significantly increased after the boost, as shown by increased counts of IFN-gamma-secreting cells in splenocytes, mesenteric lymph nodes (MLN), and vaginal samples. Furthermore, in the TC-1 tumor model, animals receiving the orally administered L. casei-PgsA-E6 showed reduced tumor size and increased survival rate versus mice receiving control (L. casei-PgsA) immunization. We also found that L. casei-PgsA-E6-induced antitumor effect was decreased by in vivo depletion of CD4(+) or CD8(+) T cells. Collectively, these results indicate that the oral administration of lactobacilli bearing the surface-displayed E6 protein induces T cell-mediated cellular immunity and antitumor effects in mice.

  1. CCL3 and CCL20-recruited dendritic cells modified by melanoma antigen gene-1 induce anti-tumor immunity against gastric cancer ex vivo and in vivo

    Directory of Open Access Journals (Sweden)

    Zhang Yanyun

    2010-04-01

    Full Text Available Abstract Background To investigate whether dendritic cell (DC precursors, recruited by injection of chemokine ligand 3 (CCL3 and CCL20, induce anti-tumor immunity against gastric cancer induced by a DC vaccine expressing melanoma antigen gene-1 (MAGE-1 ex vivo and in vivo. Methods B6 mice were injected with CCL3 and CCL20 via the tail vein. Freshly isolated F4/80-B220-CD11c+ cells cultured with cytokines were analyzed by phenotype analysis and mixed lymphocyte reaction (MLR. For adenoviral (Ad-mediated gene transduction, cultured F4/80-B220-CD11c+ cells were incubated with Ad-MAGE-1. Vaccination of stimulated DC induced T lymphocytes. The killing effect of these T cells against gastric carcinoma cells was assayed by MTT. INF-γ production was determined with an INF-γ ELISA kit. In the solid tumor and metastases model, DC-based vaccines were used for immunization after challenge with MFC cells. Tumor size, survival of mice, and number of pulmonary metastatic foci were used to assess the therapeutic effect of DC vaccines. Results F4/80-B220-CD11c+ cell numbers increased after CCL3 and CCL20 injection. Freshly isolated F4/80-B220-CD11c+ cells cultured with cytokines were phenotyically identical to typical DC and gained the capacity to stimulate allogeneic T cells. These DCs were transduced with Ad-MAGE-1, which were prepared for DC vaccines expressing tumor antigen. T lymphocytes stimulated by DCs transduced with Ad-MAGE-1 exhibited specific killing effects on gastric carcinoma cells and produced high levels of INF-γ ex vivo. In vivo, tumor sizes of the experimental group were much smaller than both the positive control group and the negative control groups (P P Conclusions CCL3 and CCL20-recruited DCs modified by adenovirus-trasnsduced, tumor-associated antigen, MAGE-1, can stimulate anti-tumor immunity specific to gastric cancer ex vivo and in vivo. This system may prove to be an efficient strategy for anti-tumor immunotherapy.

  2. Role of Tertiary Lymphoid Structures (TLS) in Anti-Tumor Immunity: Potential Tumor-Induced Cytokines/Chemokines that Regulate TLS Formation in Epithelial-Derived Cancers

    Energy Technology Data Exchange (ETDEWEB)

    Pimenta, Erica M. [Rutgers Biomedical and Health Sciences, New Jersey Medical School-Cancer Center, Newark, NJ 07103 (United States); Barnes, Betsy J., E-mail: barnesbe@njms.rutgers.edu [Department of Biochemistry and Molecular Biology, Rutgers Biomedical and Health Sciences, New Jersey Medical School-Cancer Center, Newark, NJ 07103 (United States)

    2014-04-23

    Following the successes of monoclonal antibody immunotherapies (trastuzumab (Herceptin{sup ®}) and rituximab (Rituxan{sup ®})) and the first approved cancer vaccine, Provenge{sup ®} (sipuleucel-T), investigations into the immune system and how it can be modified by a tumor has become an exciting and promising new field of cancer research. Dozens of clinical trials for new antibodies, cancer and adjuvant vaccines, and autologous T and dendritic cell transfers are ongoing in hopes of identifying ways to re-awaken the immune system and force an anti-tumor response. To date, however, few consistent, reproducible, or clinically-relevant effects have been shown using vaccine or autologous cell transfers due in part to the fact that the immunosuppressive mechanisms of the tumor have not been overcome. Much of the research focus has been on re-activating or priming cytotoxic T cells to recognize tumor, in some cases completely disregarding the potential roles that B cells play in immune surveillance or how a solid tumor should be treated to maximize immunogenicity. Here, we will summarize what is currently known about the induction or evasion of humoral immunity via tumor-induced cytokine/chemokine expression and how formation of tertiary lymphoid structures (TLS) within the tumor microenvironment may be used to enhance immunotherapy response.

  3. Role of Tertiary Lymphoid Structures (TLS) in Anti-Tumor Immunity: Potential Tumor-Induced Cytokines/Chemokines that Regulate TLS Formation in Epithelial-Derived Cancers

    International Nuclear Information System (INIS)

    Pimenta, Erica M.; Barnes, Betsy J.

    2014-01-01

    Following the successes of monoclonal antibody immunotherapies (trastuzumab (Herceptin ® ) and rituximab (Rituxan ® )) and the first approved cancer vaccine, Provenge ® (sipuleucel-T), investigations into the immune system and how it can be modified by a tumor has become an exciting and promising new field of cancer research. Dozens of clinical trials for new antibodies, cancer and adjuvant vaccines, and autologous T and dendritic cell transfers are ongoing in hopes of identifying ways to re-awaken the immune system and force an anti-tumor response. To date, however, few consistent, reproducible, or clinically-relevant effects have been shown using vaccine or autologous cell transfers due in part to the fact that the immunosuppressive mechanisms of the tumor have not been overcome. Much of the research focus has been on re-activating or priming cytotoxic T cells to recognize tumor, in some cases completely disregarding the potential roles that B cells play in immune surveillance or how a solid tumor should be treated to maximize immunogenicity. Here, we will summarize what is currently known about the induction or evasion of humoral immunity via tumor-induced cytokine/chemokine expression and how formation of tertiary lymphoid structures (TLS) within the tumor microenvironment may be used to enhance immunotherapy response

  4. Role of Tertiary Lymphoid Structures (TLS in Anti-Tumor Immunity: Potential Tumor-Induced Cytokines/Chemokines that Regulate TLS Formation in Epithelial-Derived Cancers

    Directory of Open Access Journals (Sweden)

    Erica M. Pimenta

    2014-04-01

    Full Text Available Following the successes of monoclonal antibody immunotherapies (trastuzumab (Herceptin® and rituximab (Rituxan® and the first approved cancer vaccine, Provenge® (sipuleucel-T, investigations into the immune system and how it can be modified by a tumor has become an exciting and promising new field of cancer research. Dozens of clinical trials for new antibodies, cancer and adjuvant vaccines, and autologous T and dendritic cell transfers are ongoing in hopes of identifying ways to re-awaken the immune system and force an anti-tumor response. To date, however, few consistent, reproducible, or clinically-relevant effects have been shown using vaccine or autologous cell transfers due in part to the fact that the immunosuppressive mechanisms of the tumor have not been overcome. Much of the research focus has been on re-activating or priming cytotoxic T cells to recognize tumor, in some cases completely disregarding the potential roles that B cells play in immune surveillance or how a solid tumor should be treated to maximize immunogenicity. Here, we will summarize what is currently known about the induction or evasion of humoral immunity via tumor-induced cytokine/chemokine expression and how formation of tertiary lymphoid structures (TLS within the tumor microenvironment may be used to enhance immunotherapy response.

  5. Co-delivery of PLGA encapsulated invariant NKT cell agonist with antigenic protein induce strong T cell-mediated antitumor immune responses

    NARCIS (Netherlands)

    Dolen, Y.; Kreutz, M.; Gileadi, U.; Tel, J.; Vasaturo, A.; Dinther, E.A.W. van; Hout-Kuijer, M.A. van; Cerundolo, V.; Figdor, C.G.

    2016-01-01

    Antitumor immunity can be enhanced by the coordinated release and delivery of antigens and immune-stimulating agents to antigen-presenting cells via biodegradable vaccine carriers. So far, encapsulation of TLR ligands and tumor-associated antigens augmented cytotoxic T cell (CTLs) responses. Here,

  6. Jungle Honey Enhances Immune Function and Antitumor Activity

    Science.gov (United States)

    Fukuda, Miki; Kobayashi, Kengo; Hirono, Yuriko; Miyagawa, Mayuko; Ishida, Takahiro; Ejiogu, Emenike C.; Sawai, Masaharu; Pinkerton, Kent E.; Takeuchi, Minoru

    2011-01-01

    Jungle honey (JH) is collected from timber and blossom by wild honey bees that live in the tropical forest of Nigeria. JH is used as a traditional medicine for colds, skin inflammation and burn wounds as well as general health care. However, the effects of JH on immune functions are not clearly known. Therefore, we investigated the effects of JH on immune functions and antitumor activity in mice. Female C57BL/6 mice were injected with JH (1 mg/mouse/day, seven times intra-peritoneal). After seven injections, peritoneal cells (PC) were obtained. Antitumor activity was assessed by growth of Lewis Lung Carcinoma/2 (LL/2) cells. PC numbers were increased in JH-injected mice compared to control mice. In Dot Plot analysis by FACS, a new cell population appeared in JH-injected mice. The percent of Gr-1 surface antigen and the intensity of Gr-1 antigen expression of PC were increased in JH-injected mice. The new cell population was neutrophils. JH possessed chemotactic activity for neutrophils. Tumor incidence and weight were decreased in JH-injected mice. The ratio of reactive oxygen species (ROS) producing cells was increased in JH-injected mice. The effective component in JH was fractionized by gel filtration using HPLC and had an approximate molecular weight (MW) of 261. These results suggest that neutrophils induced by JH possess potent antitumor activity mediated by ROS and the effective immune component of JH is substrate of MW 261. PMID:19141489

  7. Jungle Honey Enhances Immune Function and Antitumor Activity

    Directory of Open Access Journals (Sweden)

    Miki Fukuda

    2011-01-01

    Full Text Available Jungle honey (JH is collected from timber and blossom by wild honey bees that live in the tropical forest of Nigeria. JH is used as a traditional medicine for colds, skin inflammation and burn wounds as well as general health care. However, the effects of JH on immune functions are not clearly known. Therefore, we investigated the effects of JH on immune functions and antitumor activity in mice. Female C57BL/6 mice were injected with JH (1 mg/mouse/day, seven times intra-peritoneal. After seven injections, peritoneal cells (PC were obtained. Antitumor activity was assessed by growth of Lewis Lung Carcinoma/2 (LL/2 cells. PC numbers were increased in JH-injected mice compared to control mice. In Dot Plot analysis by FACS, a new cell population appeared in JH-injected mice. The percent of Gr-1 surface antigen and the intensity of Gr-1 antigen expression of PC were increased in JH-injected mice. The new cell population was neutrophils. JH possessed chemotactic activity for neutrophils. Tumor incidence and weight were decreased in JH-injected mice. The ratio of reactive oxygen species (ROS producing cells was increased in JH-injected mice. The effective component in JH was fractionized by gel filtration using HPLC and had an approximate molecular weight (MW of 261. These results suggest that neutrophils induced by JH possess potent antitumor activity mediated by ROS and the effective immune component of JH is substrate of MW 261.

  8. Tumor-associated antigens identified by mRNA expression profiling induce protective anti-tumor immunity

    DEFF Research Database (Denmark)

    Mathiassen, S; Lauemøller, S L; Ruhwald, M

    2001-01-01

    Defined tumor-associated antigens (TAA) are attractive targets for anti-tumor immunotherapy. Here, we describe a novel genome-wide approach to identify multiple TAA from any given tumor. A panel of transplantable thymomas was established from an inbred p53-/- mouse strain. The resulting tumors were...

  9. Radiotherapy-induced anti-tumor immunity contributes to the therapeutic efficacy of irradiation and can be augmented by CTLA-4 blockade in a mouse model.

    Directory of Open Access Journals (Sweden)

    Yuya Yoshimoto

    Full Text Available PURPOSE: There is growing evidence that tumor-specific immune responses play an important role in anti-cancer therapy, including radiotherapy. Using mouse tumor models we demonstrate that irradiation-induced anti-tumor immunity is essential for the therapeutic efficacy of irradiation and can be augmented by modulation of cytotoxic T lymphocyte (CTL activity. METHODS AND MATERIALS: C57BL/6 mice, syngeneic EL4 lymphoma cells, and Lewis lung carcinoma (LL/C cells were used. Cells were injected into the right femurs of mice. Ten days after inoculation, tumors were treated with 30 Gy of local X-ray irradiation and their growth was subsequently measured. The effect of irradiation on tumor growth delay (TGD was defined as the time (in days for tumors to grow to 500 mm3 in the treated group minus that of the untreated group. Cytokine production and serum antibodies were measured by ELISA and flow cytometry. RESULTS: In the EL4 tumor model, tumors were locally controlled by X-ray irradiation and re-introduced EL4 cells were completely rejected. Mouse EL4-specific systemic immunity was confirmed by splenocyte cytokine production and detection of tumor-specific IgG1 antibodies. In the LL/C tumor model, X-ray irradiation also significantly delayed tumor growth (TGD: 15.4 days and prolonged median survival time (MST to 59 days (versus 28 days in the non-irradiated group. CD8(+ cell depletion using an anti-CD8 antibody significantly decreased the therapeutic efficacy of irradiation (TGD, 8.7 days; MST, 49 days. Next, we examined whether T cell modulation affected the efficacy of radiotherapy. An anti-CTLA-4 antibody significantly increased the anti-tumor activity of radiotherapy (TGD was prolonged from 13.1 to 19.5 days, while anti-FR4 and anti-GITR antibodies did not affect efficacy. CONCLUSIONS: Our results indicate that tumor-specific immune responses play an important role in the therapeutic efficacy of irradiation. Immunomodulation, including CTLA-4

  10. Tumor-associated antigens identified by mRNA expression profiling induce protective anti-tumor immunity

    DEFF Research Database (Denmark)

    Mathiassen, Søren; Lauemøller, S L; Ruhwald, Morten

    2001-01-01

    Defined tumor-associated antigens (TAA) are attractive targets for anti-tumor immunotherapy. Here, we describe a novel genome-wide approach to identify multiple TAA from any given tumor. A panel of transplantable thymomas was established from an inbred p53-/- mouse strain. The resulting tumors we...... imprints, which may be used to identify patient-specific arrays of TAA. This may enable a multi-epitope based immunotherapy with improved prospects of clinical tumor rejection....

  11. Tumor-associated antigens identified by mRNA expression profiling induce protective anti-tumor immunity

    DEFF Research Database (Denmark)

    Mathiassen, S; Lauemøller, S L; Ruhwald, M

    2001-01-01

    to identify TAA, mice were immunized with mixtures of peptides representing putative cytotoxic T cell epitopes derived from one of the gene products. Indeed, such immunized mice were partially protected against subsequent tumor challenge. Despite being immunized with bona fide self antigens, no clinical signs...... imprints, which may be used to identify patient-specific arrays of TAA. This may enable a multi-epitope based immunotherapy with improved prospects of clinical tumor rejection....

  12. Combined IL-21 and Low-Dose IL-2 therapy induces anti-tumor immunity and long-term curative effects in a murine melanoma tumor model

    Directory of Open Access Journals (Sweden)

    Fox Bernard A

    2006-06-01

    Full Text Available Abstract Background In vivo studies have recently demonstrated that interleukin 21 (IL-21 enhances the anti-tumor function of T-cells and NK cells in murine tumor models, and the combined use of IL-21 and IL-15 has resulted in prolonged tumor regression and survival in mice with previously established tumors. However, the combined anti-tumor effects of IL-21 and low dose IL-2 have not been studied even though IL-2 has been approved for human use, and, at low dose administration, stimulates the proliferation of memory T cells, and does not significantly increase antigen-induced apoptosis or regulatory T cell (Treg expansion. This study examined whether recombinant IL-21 alone or in combination with low-dose IL-2 could improve the in vivo anti-tumor function of naïve, tumor-antigen specific CD8+ T cells in a gp10025–33 T cell receptor transgenic pmel murine melanoma model. Methods Congenic C57BL/6 (Ly5.2 mice bearing subcutaneous B16F10 melanoma tumors were sublethally irradiated to induce lymphopenia. After irradiation naive pmel splenocytes were adoptively transferred, and mice were immunized with bone marrow-derived dendritic cells pulsed with human gp10025–33 (hgp10025–33. Seven days after vaccination groups of mice received 5 consecutive days of intraperitoneal administration of IL-2 alone (20 × 103 IU, IL-21 alone (20 μg or IL-21 and IL-2. Control animals received no cytokine therapy. Results IL-21 alone and IL-2 alone both delayed tumor progression, but only IL-21 significantly augmented long-term survival (20% compared to the control group. However, combination therapy with IL-21 and IL-2 resulted in the highest long-term (>150 days tumor-free survival frequency of 46%. Animals that were tumor-free for > 150 days demonstrated tumor-specific protection after rechallenge with B16F10 melanoma cells. At peak expansion (21 days post vaccination, the combination of IL-21 plus IL-2 resulted in a 2- to 3-fold higher absolute number of

  13. Oncolytic Immunotherapy: Dying the Right Way is a Key to Eliciting Potent Antitumor Immunity

    Directory of Open Access Journals (Sweden)

    Zong Sheng eGuo

    2014-04-01

    Full Text Available Oncolytic viruses (OVs are novel immunotherapeutic agents whose anticancer effects come from both oncolysis and elicited antitumor immunity. OVs induce mostly immunogenic cancer cell death (ICD, including immunogenic apoptosis, necrosis/necroptosis, pyroptosis and autophagic cell death, leading to exposure of calreticulin and heat-shock proteins to the cell surface, and/or released ATP, high mobility group box-1 [HMGB1], uric acid, and other DAMPs as well as PAMPs as danger signals, along with tumor-associated antigens, to activate dendritic cells (DCs and elicit adaptive antitumor immunity. Dying the right way may greatly potentiate adaptive antitumor immunity. The mode of cancer cell death may be modulated by individual OVs and cancer cells as they often encode and express genes that inhibit/promote apoptosis, necroptosis or autophagic cell death. We can genetically engineer OVs with death-pathway-modulating genes and thus skew the infected cancer cells towards certain death pathways for the enhanced immunogenicity. Strategies combining with some standard therapeutic regimens may also change the immunological consequence of cancer cell death. In this review, we discuss recent advances in our understanding of danger signals, modes of cancer cell death induced by OVs, the induced danger signals and functions in eliciting subsequent antitumor immunity. We also discuss potential combination strategies to target cells into specific modes of ICD and enhance cancer immunogenicity, including blockade of immune checkpoints, in order to break immune tolerance, improve antitumor immunity and thus the overall therapeutic efficacy.

  14. Intermittent Metronomic Drug Schedule Is Essential for Activating Antitumor Innate Immunity and Tumor Xenograft Regression

    Directory of Open Access Journals (Sweden)

    Chong-Sheng Chen

    2014-01-01

    Full Text Available Metronomic chemotherapy using cyclophosphamide (CPA is widely associated with antiangiogenesis; however, recent studies implicate other immune-based mechanisms, including antitumor innate immunity, which can induce major tumor regression in implanted brain tumor models. This study demonstrates the critical importance of drug schedule: CPA induced a potent antitumor innate immune response and tumor regression when administered intermittently on a 6-day repeating metronomic schedule but not with the same total exposure to activated CPA administered on an every 3-day schedule or using a daily oral regimen that serves as the basis for many clinical trials of metronomic chemotherapy. Notably, the more frequent metronomic CPA schedules abrogated the antitumor innate immune and therapeutic responses. Further, the innate immune response and antitumor activity both displayed an unusually steep dose-response curve and were not accompanied by antiangiogenesis. The strong recruitment of innate immune cells by the 6-day repeating CPA schedule was not sustained, and tumor regression was abolished, by a moderate (25% reduction in CPA dose. Moreover, an ~20% increase in CPA dose eliminated the partial tumor regression and weak innate immune cell recruitment seen in a subset of the every 6-day treated tumors. Thus, metronomic drug treatment must be at a sufficiently high dose but also sufficiently well spaced in time to induce strong sustained antitumor immune cell recruitment. Many current clinical metronomic chemotherapeutic protocols employ oral daily low-dose schedules that do not meet these requirements, suggesting that they may benefit from optimization designed to maximize antitumor immune responses.

  15. Histone deacetylase inhibitor AR-42 enhances E7-specific CD8⁺ T cell-mediated antitumor immunity induced by therapeutic HPV DNA vaccination.

    Science.gov (United States)

    Lee, Sung Yong; Huang, Zhuomin; Kang, Tae Heung; Soong, Ruey-Shyang; Knoff, Jayne; Axenfeld, Ellen; Wang, Chenguang; Alvarez, Ronald D; Chen, Ching-Shih; Hung, Chien-Fu; Wu, T-C

    2013-10-01

    We have previously created a potent DNA vaccine encoding calreticulin linked to the human papillomavirus (HPV) oncogenic protein E7 (CRT/E7). While treatment with the CRT/E7 DNA vaccine generates significant tumor-specific immune responses in vaccinated mice, the potency with the DNA vaccine could potentially be improved by co-administration of a histone deacetylase inhibitor (HDACi) as HDACi has been shown to increase the expression of MHC class I and II molecules. Thus, we aimed to determine whether co-administration of a novel HDACi, AR-42, with therapeutic HPV DNA vaccines could improve the activation of HPV antigen-specific CD8(+) T cells, resulting in potent therapeutic antitumor effects. To do so, HPV-16 E7-expressing murine TC-1 tumor-bearing mice were treated orally with AR-42 and/or CRT/E7 DNA vaccine via gene gun. Mice were monitored for E7-specific CD8(+) T cell immune responses and antitumor effects. TC-1 tumor-bearing mice treated with AR-42 and CRT/E7 DNA vaccine experienced longer survival, decreased tumor growth, and enhanced E7-specific immune response compared to mice treated with AR-42 or CRT/E7 DNA vaccine alone. Additionally, treatment of TC-1 cells with AR-42 increased the surface expression of MHC class I molecules and increased the susceptibility of tumor cells to the cytotoxicity of E7-specific T cells. This study indicates the ability of AR-42 to significantly enhance the potency of the CRT/E7 DNA vaccine by improving tumor-specific immune responses and antitumor effects. Both AR-42 and CRT/E7 DNA vaccines have been used in independent clinical trials; the current study serves as foundation for future clinical trials combining both treatments in cervical cancer therapy. AR-42, a novel HDAC inhibitor, enhances potency of therapeutic HPV DNA vaccines AR-42 treatment leads to strong E7-specific CD8+ T cell immune responses AR-42 improves tumor-specific immunity and antitumor effects elicited by HPV DNA vaccine AR-42 is more potent than

  16. Dendritic Cells Genetically Modified with an Adenovirus Vector Encoding the cDNA for a Model Antigen Induce Protective and Therapeutic Antitumor Immunity

    Science.gov (United States)

    Song, Wenru; Kong, Hwai-Loong; Carpenter, Heather; Torii, Hideshi; Granstein, Richard; Rafii, Shahin; Moore, Malcolm A.S.; Crystal, Ronald G.

    1997-01-01

    Dendritic cells (DCs) are potent antigen-presenting cells that play a critical role in the initiation of antitumor immune responses. In this study, we show that genetic modifications of a murine epidermis-derived DC line and primary bone marrow–derived DCs to express a model antigen β-galactosidase (βgal) can be achieved through the use of a replication-deficient, recombinant adenovirus vector, and that the modified DCs are capable of eliciting antigen-specific, MHC-restricted CTL responses. Importantly, using a murine metastatic lung tumor model with syngeneic colon carcinoma cells expressing βgal, we show that immunization of mice with the genetically modified DC line or bone marrow DCs confers potent protection against a lethal tumor challenge, as well as suppression of preestablished tumors, resulting in a significant survival advantage. We conclude that genetic modification of DCs to express antigens that are also expressed in tumors can lead to antigen-specific, antitumor killer cells, with a concomitant resistance to tumor challenge and a decrease in the size of existing tumors. PMID:9334364

  17. The role of radiotherapy for the induction of antitumor immune responses

    International Nuclear Information System (INIS)

    Multhoff, G.; Helmholtz-Zentrum Muenchen; Gaipl, U.S.; Niedermann, G.

    2012-01-01

    Effective radiotherapy is aimed to control the growth of the primary carcinoma and to induce a long-term specific antitumor immune response against the primary tumor, recurrence and metastases. The contribution covers the following issues: T cells and tumor specific immune responses, dendritic cells (DCs) start adaptive immune responses, NK (natural killer) cells for HLA independent tumor control, abscopal effects of radiotherapy, combination of radiotherapy and immune therapy, radiotherapy contribution to the induction of immunogenic cell death, combinability of radiotherapy and DC activation, combinability of radiotherapy and NK cell therapy. It turns out that the combination of radio-chemotherapy and immune therapy can change the microenvironment initiating antitumor immune reactions that inhibit the recurrence risk and the development of metastases.

  18. Interleukin-6 Induced "Acute" Phenotypic Microenvironment Promotes Th1 Anti-Tumor Immunity in Cryo-Thermal Therapy Revealed By Shotgun and Parallel Reaction Monitoring Proteomics.

    Science.gov (United States)

    Xue, Ting; Liu, Ping; Zhou, Yong; Liu, Kun; Yang, Li; Moritz, Robert L; Yan, Wei; Xu, Lisa X

    2016-01-01

    Cryo-thermal therapy has been emerged as a promising novel therapeutic strategy for advanced breast cancer, triggering higher incidence of tumor regression and enhanced remission of metastasis than routine treatments. To better understand its anti-tumor mechanism, we utilized a spontaneous metastatic mouse model and quantitative proteomics to compare N-glycoproteome changes in 94 serum samples with and without treatment. We quantified 231 highly confident N-glycosylated proteins using iTRAQ shotgun proteomics. Among them, 53 showed significantly discriminated regulatory patterns over the time course, in which the acute phase response emerged as the most enhanced pathway. The anti-tumor feature of the acute response was further investigated using parallel reaction monitoring target proteomics and flow cytometry on 23 of the 53 significant proteins. We found that cryo-thermal therapy reset the tumor chronic inflammation to an "acute" phenotype, with up-regulation of acute phase proteins including IL-6 as a key regulator. The IL-6 mediated "acute" phenotype transformed IL-4 and Treg-promoting ICOSL expression to Th1-promoting IFN-γ and IL-12 production, augmented complement system activation and CD86(+)MHCII(+) dendritic cells maturation and enhanced the proliferation of Th1 memory cells. In addition, we found an increased production of tumor progression and metastatic inhibitory proteins under such "acute" environment, favoring the anti-metastatic effect. Moreover, cryo-thermal on tumors induced the strongest "acute" response compared to cryo/hyperthermia alone or cryo-thermal on healthy tissues, accompanying by the most pronounced anti-tumor immunological effect. In summary, we demonstrated that cryo-thermal therapy induced, IL-6 mediated "acute" microenvironment shifted the tumor chronic microenvironment from Th2 immunosuppressive and pro-tumorigenic to Th1 immunostimulatory and tumoricidal state. Moreover, the magnitude of "acute" and "danger" signals play a key

  19. How Does Ionizing Irradiation Contribute to the Induction of Anti-Tumor Immunity?

    International Nuclear Information System (INIS)

    Rubner, Yvonne; Wunderlich, Roland; Rühle, Paul-Friedrich; Kulzer, Lorenz; Werthmöller, Nina; Frey, Benjamin; Weiss, Eva-Maria; Keilholz, Ludwig; Fietkau, Rainer; Gaipl, Udo S.

    2012-01-01

    Radiotherapy (RT) with ionizing irradiation is commonly used to locally attack tumors. It induces a stop of cancer cell proliferation and finally leads to tumor cell death. During the last years it has become more and more evident that besides a timely and locally restricted radiation-induced immune suppression, a specific immune activation against the tumor and its metastases is achievable by rendering the tumor cells visible for immune attack. The immune system is involved in tumor control and we here outline how RT induces anti-inflammation when applied in low doses and contributes in higher doses to the induction of anti-tumor immunity. We especially focus on how local irradiation induces abscopal effects. The latter are partly mediated by a systemic activation of the immune system against the individual tumor cells. Dendritic cells are the key players in the initiation and regulation of adaptive anti-tumor immune responses. They have to take up tumor antigens and consecutively present tumor peptides in the presence of appropriate co-stimulation. We review how combinations of RT with further immune stimulators such as AnnexinA5 and hyperthermia foster the dendritic cell-mediated induction of anti-tumor immune responses and present reasonable combination schemes of standard tumor therapies with immune therapies. It can be concluded that RT leads to targeted killing of the tumor cells and additionally induces non-targeted systemic immune effects. Multimodal tumor treatments should therefore tend to induce immunogenic tumor cell death forms within a tumor microenvironment that stimulates immune cells.

  20. Effects of Androgen Ablation on Anti-Tumor Immunity

    National Research Council Canada - National Science Library

    Kast, Martin

    2004-01-01

    .... This AA induced autoimmune-like response exerts limited anti-tumor activity in a murine prostate cancer model, but could be synergistic with CTLA-4 blockade that promotes the development of autoreactive T cell...

  1. Cryo-ablation improves anti-tumor immunity through recovering tumor educated dendritic cells in tumor-draining lymph nodes.

    Science.gov (United States)

    He, Xiao-Zheng; Wang, Qi-Fu; Han, Shuai; Wang, Hui-Qing; Ye, Yong-Yi; Zhu, Zhi-Yuan; Zhang, Shi-Zhong

    2015-01-01

    In addition to minimally invasive destruction of tumors, cryo-ablation of tumors to some extent modulated anti-tumor immunity. Cryo-ablated tumors in glioma mice models induced anti-tumor cellular immunologic response which increases the percentage of CD3(+) and CD4(+)T cells in blood as well as natural killer cells. As a crucial role in triggering anti-tumor immunity, dendritic cells (DCs) were educated by tumors to adopt a tolerance phenotype which helps the tumor escape from immune monitoring. This study aims to study whether cryo-ablation could influence the tolerogenic DCs, and influence anti-tumor immunity in tumor-draining lymph nodes (TDLNs). Using the GL261 subcutaneous glioma mouse model, we created a tumor bearing group, cryo-ablation group, and surgery group. We analyzed alteration in phenotype and function of tolerogenic DCs, and evaluated the factors of anti-tumor immunity inhibition. DCs in TDLNs in GL261 subcutaneous glioma mouse model expressed tolerogenic phenotype. In contrast to surgery, cryo-ablation improved the quantity and quality of these tolerogenic DCs. Moreover, the DCs decreased the expression of intracellular interleukin-10 (IL-10) and extra-cellular IL-10. In vitro, DCs from the cryo-ablation group recovered their specific function and induced potent anti-tumor immunity through triggering T cells. In vivo, cryo-ablation showed weak anti-tumor immunity, only inhibiting the growth of rechallenged tumors. But many IL-10-low DCs, rather than IL-10-high DCs, infiltrated the tumors. More importantly, Tregs inhibited the performance of these DCs; and depletion of Tregs greatly improved anti-tumor immunity in vivo. Cryo-ablation could recover function of tumor induced tolerogenic DCs in vitro; and depletion of Tregs could improve this anti-tumor effect in vivo. The Tregs/CD4(+)T and Tregs/CD25(+)T cells in TDLNs inhibit DCs' activity and function.

  2. Introduction of a point mutation into an HLA class I single-chain trimer induces enhancement of CTL priming and antitumor immunity

    Directory of Open Access Journals (Sweden)

    Masanori Matsui

    2014-01-01

    Full Text Available We previously discovered one particular HLA-A*02:01 mutant that enhanced peptide-specific cytotoxic T lymphocyte (CTL recognition in vitro compared to wild-type HLA-A*02:01. This mutant contains a single amino acid substitution from histidine to leucine at position 74 (H74L that is located in the peptide-binding groove. To investigate the effect of the H74L mutation on the in vivo CTL priming, we took advantage of the technology of the HLA class I single-chain trimer (SCT in which three components involving a peptide, β2 microglobulin and the HLA class I heavy chain are joined together via flexible linkers. We generated recombinant adenovirus expressing SCT comprised influenza A matrix protein (FMP-derived peptide, β2 microglobulin and the H74L heavy chain. HLA-A*02:01 transgenic mice were immunized with the adenovirus, and the induction of peptide-specific CTLs and antitumor immunity was investigated. It was clearly shown that the H74L mutation enabled the HLA-A*02:01 SCT molecule to dramatically enhance both in vivo priming of FMP-specific CTLs and protection against a lethal challenge of tumor cells expressing FMP. These data present the first evidence that a simple point mutation in the HLA class I heavy chain of SCT is beneficial for improving CTL-based immunotherapy and prophylaxis to control tumors.

  3. The role of radiotherapy for the induction of antitumor immune responses; Die Rolle der Strahlentherapie bei der Induktion von Antitumor-Immunantworten

    Energy Technology Data Exchange (ETDEWEB)

    Multhoff, G. [Technische Univ. Muenchen, Klinikum rechts der Isar (Germany). Klinik fuer Strahlentherapie und Radiologische Onkologie, Experimentelle Radioonkologie; Helmholtz-Zentrum Muenchen (HMGU) (Germany). Klinische Kooperationsgruppe: ' Angeborene Immunantwort in der Tumorbiologie' ; Gaipl, U.S. [Universitaetsklinikum Erlangen (Germany). Strahlenklinik/Radioonkologie, Strahlen-Immunbiologie; Niedermann, G. [Universitaetsklinikum Freiburg (Germany). Klinik fuer Strahlenheilkunde, Sektion fuer Klinische und Experimentelle Strahlenbiologie

    2012-11-15

    Effective radiotherapy is aimed to control the growth of the primary carcinoma and to induce a long-term specific antitumor immune response against the primary tumor, recurrence and metastases. The contribution covers the following issues: T cells and tumor specific immune responses, dendritic cells (DCs) start adaptive immune responses, NK (natural killer) cells for HLA independent tumor control, abscopal effects of radiotherapy, combination of radiotherapy and immune therapy, radiotherapy contribution to the induction of immunogenic cell death, combinability of radiotherapy and DC activation, combinability of radiotherapy and NK cell therapy. It turns out that the combination of radio-chemotherapy and immune therapy can change the microenvironment initiating antitumor immune reactions that inhibit the recurrence risk and the development of metastases.

  4. Chloroquine modulates antitumor immune response by resetting tumor-associated macrophages toward M1 phenotype.

    Science.gov (United States)

    Chen, Degao; Xie, Jing; Fiskesund, Roland; Dong, Wenqian; Liang, Xiaoyu; Lv, Jiadi; Jin, Xun; Liu, Jinyan; Mo, Siqi; Zhang, Tianzhen; Cheng, Feiran; Zhou, Yabo; Zhang, Huafeng; Tang, Ke; Ma, Jingwei; Liu, Yuying; Huang, Bo

    2018-02-28

    Resetting tumor-associated macrophages (TAMs) is a promising strategy to ameliorate the immunosuppressive tumor microenvironment and improve innate and adaptive antitumor immunity. Here we show that chloroquine (CQ), a proven anti-malarial drug, can function as an antitumor immune modulator that switches TAMs from M2 to tumor-killing M1 phenotype. Mechanistically, CQ increases macrophage lysosomal pH, causing Ca 2+ release via the lysosomal Ca 2+ channel mucolipin-1 (Mcoln1), which induces the activation of p38 and NF-κB, thus polarizing TAMs to M1 phenotype. In parallel, the released Ca 2+ activates transcription factor EB (TFEB), which reprograms the metabolism of TAMs from oxidative phosphorylation to glycolysis. As a result, CQ-reset macrophages ameliorate tumor immune microenvironment by decreasing immunosuppressive infiltration of myeloid-derived suppressor cells and Treg cells, thus enhancing antitumor T-cell immunity. These data illuminate a previously unrecognized antitumor mechanism of CQ, suggesting a potential new macrophage-based tumor immunotherapeutic modality.

  5. Radiotherapy and antitumoral immunity. Fundamentals of immunooncology

    International Nuclear Information System (INIS)

    Klimovich, V.B.

    1982-01-01

    The fundamental states of immunooncology are described briefly: conception of immunologic inspection, antiblastomic immunologic factors, antigeny of tumor cells and mechanisms of slipping out of immune inspection, problastomic immunologic factors. The conclusion is made that tumor formation and extenstion go on under the action of opposite directed but not mutually exclusive factors of immunologic nature. Growth rate and regression of neoplasm are determined by balance between antiblastomic mechanism activity and activity of problastomic factors and factors of immunoresistant neoplasms

  6. SCIB2, an antibody DNA vaccine encoding NY-ESO-1 epitopes, induces potent antitumor immunity which is further enhanced by checkpoint blockade.

    Science.gov (United States)

    Xue, Wei; Metheringham, Rachael L; Brentville, Victoria A; Gunn, Barbara; Symonds, Peter; Yagita, Hideo; Ramage, Judith M; Durrant, Lindy G

    2016-06-01

    Checkpoint blockade has demonstrated promising antitumor responses in approximately 10-40% of patients. However, the majority of patients do not make a productive immune response to their tumors and do not respond to checkpoint blockade. These patients may benefit from an effective vaccine that stimulates high-avidity T cell responses in combination with checkpoint blockade. We have previously shown that incorporating TRP-2 and gp100 epitopes into the CDR regions of a human IgG1 DNA (ImmunoBody®: IB) results in significant tumor regression both in animal models and patients. This vaccination strategy is superior to others as it targets antigen to antigen-presenting cells and stimulates high-avidity T cell responses. To broaden the application of this vaccination strategy, 16 NY-ESO-1 epitopes, covering over 80% of HLA phenotypes, were incorporated into the IB (SCIB2). They produced higher frequency and avidity T cell responses than peptide vaccination. These T cells were of sufficient avidity to kill NY-ESO-1-expressing tumor cells, and in vivo controlled the growth of established B16-NY-ESO-1 tumors, resulting in long-term survival (35%). When SCIB2 was given in combination with Treg depletion, CTLA-4 blockade or PD-1 blockade, long-term survival from established tumors was significantly enhanced to 56, 67 and 100%, respectively. Translating these responses into the clinic by using a combination of SCIB2 vaccination and checkpoint blockade can only further improve clinical responses.

  7. Critical role for Sec22b-dependent antigen cross-presentation in antitumor immunity.

    Science.gov (United States)

    Alloatti, Andrés; Rookhuizen, Derek C; Joannas, Leonel; Carpier, Jean-Marie; Iborra, Salvador; Magalhaes, Joao G; Yatim, Nader; Kozik, Patrycja; Sancho, David; Albert, Matthew L; Amigorena, Sebastian

    2017-08-07

    CD8 + T cells mediate antigen-specific immune responses that can induce rejection of solid tumors. In this process, dendritic cells (DCs) are thought to take up tumor antigens, which are processed into peptides and loaded onto MHC-I molecules, a process called "cross-presentation." Neither the actual contribution of cross-presentation to antitumor immune responses nor the intracellular pathways involved in vivo are clearly established because of the lack of experimental tools to manipulate this process. To develop such tools, we generated mice bearing a conditional DC-specific mutation in the sec22b gene, a critical regulator of endoplasmic reticulum-phagosome traffic required for cross-presentation. DCs from these mice show impaired cross-presentation ex vivo and defective cross-priming of CD8 + T cell responses in vivo. These mice are also defective for antitumor immune responses and are resistant to treatment with anti-PD-1. We conclude that Sec22b-dependent cross-presentation in DCs is required to initiate CD8 + T cell responses to dead cells and to induce effective antitumor immune responses during anti-PD-1 treatment in mice. © 2017 Alloatti et al.

  8. The impact of radiation therapy on the antitumor immunity: local effects and systemic consequences.

    Science.gov (United States)

    Lumniczky, Katalin; Sáfrány, Géza

    2015-01-01

    The main antitumor efficacy of irradiation relies in its direct cytotoxic effect. Increasing evidence indicates a systemic effect of radiation though, mediated mainly by the immune system. In this review we wish to focus on the radiotherapy induced modifications of the soluble and cellular mediators of the antitumor immune response and summarize some of the mechanisms by which radiation driven local and systemic bystander effects can influence tumor immunogenicity. In different tumor types due to the intrinsic immunogenicity of the tumor cells and the immunological characteristics of the tumor microenvironment, different radiation induced immune modulatory mechanisms are predominant. Radiation most probably can only amplify or augment a pro-immunogenic phenotype and can hardly change by itself a net immune suppressing environment into an immune stimulating one. This immune modulatory potential of radiotherapy could be exploited in tumor treatment by developing combined radiotherapeutic and immunotherapeutic approaches. The last few years showed a dramatic increase in the knowledge of radiation induced out-of field and systemic effects, which foresees a rapid progress in the development and clinical application of these new, combined therapies for cancer cure. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  9. Synthetic RORγ agonists regulate multiple pathways to enhance antitumor immunity

    Science.gov (United States)

    Hu, Xiao; Liu, Xikui; Moisan, Jacques; Wang, Yahong; Lesch, Charles A.; Spooner, Chauncey; Morgan, Rodney W.; Zawidzka, Elizabeth M.; Mertz, David; Bousley, Dick; Majchrzak, Kinga; Kryczek, Ilona; Taylor, Clarke; Van Huis, Chad; Skalitzky, Don; Hurd, Alexander; Aicher, Thomas D.; Toogood, Peter L.; Glick, Gary D.; Paulos, Chrystal M.; Zou, Weiping; Carter, Laura L.

    2016-01-01

    ABSTRACT RORγt is the key transcription factor controlling the development and function of CD4+ Th17 and CD8+ Tc17 cells. Across a range of human tumors, about 15% of the CD4+ T cell fraction in tumor-infiltrating lymphocytes are RORγ+ cells. To evaluate the role of RORγ in antitumor immunity, we have identified synthetic, small molecule agonists that selectively activate RORγ to a greater extent than the endogenous agonist desmosterol. These RORγ agonists enhance effector function of Type 17 cells by increasing the production of cytokines/chemokines such as IL-17A and GM-CSF, augmenting expression of co-stimulatory receptors like CD137, CD226, and improving survival and cytotoxic activity. RORγ agonists also attenuate immunosuppressive mechanisms by curtailing Treg formation, diminishing CD39 and CD73 expression, and decreasing levels of co-inhibitory receptors including PD-1 and TIGIT on tumor-reactive lymphocytes. The effects of RORγ agonists were not observed in RORγ−/− T cells, underscoring the selective on-target activity of the compounds. In vitro treatment of tumor-specific T cells with RORγ agonists, followed by adoptive transfer to tumor-bearing mice is highly effective at controlling tumor growth while improving T cell survival and maintaining enhanced IL-17A and reduced PD-1 in vivo. The in vitro effects of RORγ agonists translate into single agent, immune system-dependent, antitumor efficacy when compounds are administered orally in syngeneic tumor models. RORγ agonists integrate multiple antitumor mechanisms into a single therapeutic that both increases immune activation and decreases immune suppression resulting in robust inhibition of tumor growth. Thus, RORγ agonists represent a novel immunotherapy approach for cancer. PMID:28123897

  10. Induction of anti-tumor immunity by trifunctional antibodies in patients with peritoneal carcinomatosis

    Directory of Open Access Journals (Sweden)

    Lindhofer Horst

    2009-02-01

    Full Text Available Abstract Peritoneal carcinomatosis (PC from epithelial tumors is a fatal diagnosis without efficient treatment. Trifunctional antibodies (trAb are novel therapeutic approaches leading to a concerted anti-tumor activity resulting in tumor cell destruction. In addition, preclinical data in mouse tumor models demonstrated the induction of long lasting tumor immunity after treatment with trAb. We describe the induction of anti-tumor specific T-lymphocytes after intraperitoneal administration of trAb in patients with PC. 9 patients with progressive PC from gastric (n = 6 and ovarian cancer (n = 2, and cancer of unknown primary (n = 1 received 3 escalating doses of trAb after surgery and/or ineffective chemotherapy. The trAb EpCAM × CD3 (10, 20, 40 μg or HER2/neu × CD3 (10, 40, 80 μg were applicated by intraperitoneal infusion. Four weeks after the last trAb application, all patients were restimulated by subdermal injection of trAb + autologous PBMC + irradiated autologous tumor cells. Immunological reactivity was tested by analyzing PBMC for specific tumor reactive CD4+/CD8+ T lymphocytes using an IFN-γ secretion assay. In 5 of 9 patients, tumor reactive CD4+/CD8+ T-lymphocytes increased significantly, indicating specific anti-tumor immunity. A clinical response (stable disease, partial regression has been observed in 5 of 9 patients, with a mean time to progression of 3.6 months. Follow-up showed a mean survival of 11.8 months (median 8.0 months after trAb therapy. TrAb are able to induce anti-tumor immunity after intraperitoneal application and restimulation. The induction of long-lasting anti-tumor immunity may provide an additional benefit of the intraperitoneal therapy with trAb and should be further elevated in larger clinical trials.

  11. Antitumor mechanisms of metformin: Signaling, metabolism, immunity and beyond

    Directory of Open Access Journals (Sweden)

    Ismael Samudio

    2010-08-01

    Full Text Available Metformin is a synthetic biguanide first described in the 1920´s as a side product of the synthesis of N,N-dimethylguanidine. Like otherrelated biguanides, metformin displays antihyperglycemic properties, and has become the most widely prescribed oral antidiabetic medicinearound the world. Intriguing recent evidence suggests that metformin has chemopreventive and direct antitumor properties, and severalongoing clinical studies around the world are using this agent alone or in combination with chemotherapeutic schemes to determineprospectively its safety and efficacy in the treatment of human cancer. Notably, immune activating effects of metformin have recently beendescribed, and may support a notion put forth in the 1950s that this agent possessed antiviral and antimalarial effects. However, how theseeffects may contribute to its observed antitumor effects in retrospective studies has not been discussed. Mechanistically, metformin has beenshown to activate liver kinase B1 (LKB1 and its downstream target AMP-activated kinase (AMPK. The activation of AMPK has beenproposed to mediate metformin´s glucose lowering effect, although recent evidence suggests that this agent can inhibit electron transport inhepatocyte mitochondria resulting in AMPK-independent inhibition of hepatic gluconeogenesis. Likewise, albeit activation of AMPK andthe resulting inhibition of the mammalian target of rapamycin (mTOR signaling have been suggested to mediate the antitumor effects ofmetformin, AMPK-independent growth inhibitory properties of this agent in tumor cells have also been described. Here we present a briefreview of the signaling, metabolic, and immune effects of metformin and discuss how their interplay may orchestrate the antitumor effectsof this agent. In addition, we provide the rationale for a compassionate use study of metformin in combination with metronomic chemotherapy.

  12. Oncogenic pathways that affect antitumor immune response and immune checkpoint blockade therapy.

    Science.gov (United States)

    Zhao, Xianda; Subramanian, Subbaya

    2018-01-01

    Mechanistic insights of cancer immunology have led to the development of immune checkpoint blockade therapy (ICBT), which has elicited a remarkable clinical response in some cancer patients. Increasing evidence suggests that activation of oncogenic pathways, such as RAS/RAF/MAPK and PI3K signaling, impairs the antitumor immune response. Such oncogenic signaling, in turn, activates many inhibitory factors, including expression of immune checkpoint genes-allowing active infiltration of immunosuppressive cells into the tumor environment and inducing resistance against T-cell killing. In preclinical tumor models, effective targeting of oncogenic pathways has enhanced the response to ICBT. Ongoing clinical trials are now evaluating combination therapy (i.e., the use of oncogenic pathway inhibitors in combination with ICBT). However, more translational and clinical research is needed, to optimize ICBT doses and sequence, minimize toxicity, and assess the impact on study participants of certain genetic backgrounds. Also, it is crucial to understand whether wild-type tumors with elevated oncogenic signaling will respond to combination therapy. Insights gained through current and future translational studies will provide the scientific premise and rationale to target 1 or more oncogenic pathways in ICBT-resistant tumors, thus enabling more human patients to benefit from combination therapy. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Synthetic ROR? agonists regulate multiple pathways to enhance antitumor immunity

    OpenAIRE

    Hu, Xiao; Liu, Xikui; Moisan, Jacques; Wang, Yahong; Lesch, Charles A.; Spooner, Chauncey; Morgan, Rodney W.; Zawidzka, Elizabeth M.; Mertz, David; Bousley, Dick; Majchrzak, Kinga; Kryczek, Ilona; Taylor, Clarke; Van Huis, Chad; Skalitzky, Don

    2016-01-01

    ABSTRACT ROR?t is the key transcription factor controlling the development and function of CD4+ Th17 and CD8+ Tc17 cells. Across a range of human tumors, about 15% of the CD4+ T cell fraction in tumor-infiltrating lymphocytes are ROR?+ cells. To evaluate the role of ROR? in antitumor immunity, we have identified synthetic, small molecule agonists that selectively activate ROR? to a greater extent than the endogenous agonist desmosterol. These ROR? agonists enhance effector function of Type 17...

  14. Hijacker of the Antitumor Immune Response: Autophagy Is Showing Its Worst Facet.

    Science.gov (United States)

    Viry, Elodie; Noman, Muhammad Zaeem; Arakelian, Tsolère; Lequeux, Audrey; Chouaib, Salem; Berchem, Guy; Moussay, Etienne; Paggetti, Jérôme; Janji, Bassam

    2016-01-01

    Macroautophagy (hereafter referred to as autophagy) is a housekeeping process constitutively executed at basal level in all cells to promote cellular homeostasis by regulating organelle and protein turnover. However, autophagy deregulation caused by several stress factors, such as hypoxia, is prevalent in many cancers. It is now well established that autophagy can act as tumor suppressor or tumor promoter depending on tumor type, stage, and genetic context. In developed tumors, autophagy promotes the survival of cancer cells and therefore operates as a cell resistance mechanism. Emerging evidence point to the prominent role of autophagy in disabling the antitumor immune response by multiple overlapping mechanisms leading to tumor escape from immune cell attack mediated by both natural killer cells and cytotoxic T-lymphocytes. Such a role has inspired significant interest in applying anti-autophagy therapies as an entirely new approach to overcome tumor escape from immune surveillance, which constitutes so far a major challenge in developing more effective cancer immunotherapies. In this review, we will summarize recent reports describing how tumor cells, by activating autophagy, manage to hijack the immune system. In particular, we will focus on the emerging role of hypoxia-induced autophagy in shaping the antitumor immune response and in allowing tumor cells to outmaneuver an effective immune response and escape immunosurveillance. In keeping with this, we strongly believe that autophagy represents an attractive future therapeutic target to develop innovative and effective cancer immunotherapeutic approaches.

  15. TLR2-dependent induction of IL-10 and Foxp3+ CD25+ CD4+ regulatory T cells prevents effective anti-tumor immunity induced by Pam2 lipopeptides in vivo.

    Directory of Open Access Journals (Sweden)

    Sayuri Yamazaki

    Full Text Available 16 S-[2,3-bis(palmitoylpropyl]cysteine (Pam2 lipopeptides act as toll-like receptor (TLR2/6 ligands and activate natural killer (NK cells and dendritic cells (DCs to produce inflammatory cytokines and cytotoxic NK activity in vitro. However, in this study, we found that systemic injection of Pam2 lipopeptides was not effective for the suppression of NK-sensitive B16 melanomas in vivo. When we investigated the immune suppressive mechanisms, systemic injection of Pam2 lipopeptides induced IL-10 in a TLR2-dependent manner. The Pam2 lipopeptides increased the frequencies of Foxp3(+CD4(+ regulatory T (T reg cells in a TLR2- and IL-10- dependent manner. The T reg cells from Pam2-lipopeptide injected mice maintained suppressor activity. Pam2 lipopeptides, plus the depletion of T reg with an anti-CD25 monoclonal antibody, improved tumor growth compared with Pam2 lipopeptides alone. In conclusion, our data suggested that systemic treatment of Pam2 lipopeptides promoted IL-10 production and T reg function, which suppressed the effective induction of anti-tumor immunity in vivo. It is necessary to develop an adjuvant that does not promote IL-10 and T reg function in vivo for the future establishment of an anti-cancer vaccine.

  16. A tritherapy combination of inactivated allogeneic leukocytes infusion and cell vaccine with cyclophosphamide in a sequential regimen enhances antitumor immunity

    OpenAIRE

    Yishu Tang; Wenbo Ma; Chunxia Zhou; Dongmei Wang; Shuren Zhang

    2018-01-01

    Background: Tumor-induced immunosuppression can impede tumor-specific immune responses and limit the effects of cancer immunotherapy. The aim of this study was to investigate the possible effects of sequential chemoimmunotherapeutic strategies to enhance antitumor immune responses. Methods: Using the E7-expressing tumor TC-1 as the tumor model, the treatment groups were divided into the following groups: (1) inactivated allogeneic leukocyte infusion (ALI), (2) ALI + MMC-inactivated TC-1 cell ...

  17. Antitumor activity of orally administered maitake α-glucan by stimulating antitumor immune response in murine tumor.

    Directory of Open Access Journals (Sweden)

    Yuki Masuda

    Full Text Available Maitake α-glucan, YM-2A, isolated from Grifola frondosa, has been characterized as a highly α-1,6-branched α-1,4 glucan. YM-2A has been shown to possess an anti-virus effect in mice; however, it does not directly inhibit growth of the virus in vitro, indicating that the anti-virus effect of YM-2A might be associated with modulation of the host immune system. In this study, we found that oral administration of YM-2A could inhibit tumor growth and improve survival rate in two distinct mouse models of colon-26 carcinoma and B16 melanoma. Orally administered YM-2A enhanced antitumor immune response by increasing INF-γ-expressing CD4+ and CD8+ cells in the spleen and INF-γ-expressing CD8+ cells in tumor-draining lymph nodes. In vitro study showed that YM-2A directly activated splenic CD11b+ myeloid cells, peritoneal macrophages and bone marrow-derived dendritic cells, but did not affect splenic CD11b- lymphocytes or colon-26 tumor cells. YM-2A is more slowly digested by pancreatic α-amylase than are amylopectin and rabbit liver glycogen, and orally administered YM-2A enhanced the expression of MHC class II and CD86 on dendritic cells and the expression of MHC class II on macrophages in Peyer's patches. Furthermore, in vitro stimulation of YM-2A increased the expression of pro-inflammatory cytokines in Peyer's patch CD11c+ cells. These results suggest that orally administered YM-2A can activate dendritic cells and macrophages in Peyer's patches, inducing systemic antitumor T-cell response. Thus, YM-2A might be a candidate for an oral therapeutic agent in cancer immunotherapy.

  18. Antitumor effect of malaria parasite infection in a murine Lewis lung cancer model through induction of innate and adaptive immunity.

    Directory of Open Access Journals (Sweden)

    Lili Chen

    Full Text Available BACKGROUND: Lung cancer is the most common malignancy in humans and its high fatality means that no effective treatment is available. Developing new therapeutic strategies for lung cancer is urgently needed. Malaria has been reported to stimulate host immune responses, which are believed to be efficacious for combating some clinical cancers. This study is aimed to provide evidence that malaria parasite infection is therapeutic for lung cancer. METHODOLOGY/PRINCIPAL FINDINGS: Antitumor effect of malaria infection was examined in both subcutaneously and intravenously implanted murine Lewis lung cancer (LLC model. The results showed that malaria infection inhibited LLC growth and metastasis and prolonged the survival of tumor-bearing mice. Histological analysis of tumors from mice infected with malaria revealed that angiogenesis was inhibited, which correlated with increased terminal deoxynucleotidyl transferase-mediated (TUNEL staining and decreased Ki-67 expression in tumors. Through natural killer (NK cell cytotoxicity activity, cytokine assays, enzyme-linked immunospot assay, lymphocyte proliferation, and flow cytometry, we demonstrated that malaria infection provided anti-tumor effects by inducing both a potent anti-tumor innate immune response, including the secretion of IFN-γ and TNF-α and the activation of NK cells as well as adaptive anti-tumor immunity with increasing tumor-specific T-cell proliferation and cytolytic activity of CD8(+ T cells. Notably, tumor-bearing mice infected with the parasite developed long-lasting and effective tumor-specific immunity. Consequently, we found that malaria parasite infection could enhance the immune response of lung cancer DNA vaccine pcDNA3.1-hMUC1 and the combination produced a synergistic antitumor effect. CONCLUSIONS/SIGNIFICANCE: Malaria infection significantly suppresses LLC growth via induction of innate and adaptive antitumor responses in a mouse model. These data suggest that the malaria

  19. Antitumor Effect of Malaria Parasite Infection in a Murine Lewis Lung Cancer Model through Induction of Innate and Adaptive Immunity

    Science.gov (United States)

    Chen, Lili; He, Zhengxiang; Qin, Li; Li, Qinyan; Shi, Xibao; Zhao, Siting; Chen, Ling; Zhong, Nanshan; Chen, Xiaoping

    2011-01-01

    Background Lung cancer is the most common malignancy in humans and its high fatality means that no effective treatment is available. Developing new therapeutic strategies for lung cancer is urgently needed. Malaria has been reported to stimulate host immune responses, which are believed to be efficacious for combating some clinical cancers. This study is aimed to provide evidence that malaria parasite infection is therapeutic for lung cancer. Methodology/Principal Findings Antitumor effect of malaria infection was examined in both subcutaneously and intravenously implanted murine Lewis lung cancer (LLC) model. The results showed that malaria infection inhibited LLC growth and metastasis and prolonged the survival of tumor-bearing mice. Histological analysis of tumors from mice infected with malaria revealed that angiogenesis was inhibited, which correlated with increased terminal deoxynucleotidyl transferase-mediated (TUNEL) staining and decreased Ki-67 expression in tumors. Through natural killer (NK) cell cytotoxicity activity, cytokine assays, enzyme-linked immunospot assay, lymphocyte proliferation, and flow cytometry, we demonstrated that malaria infection provided anti-tumor effects by inducing both a potent anti-tumor innate immune response, including the secretion of IFN-γ and TNF-α and the activation of NK cells as well as adaptive anti-tumor immunity with increasing tumor-specific T-cell proliferation and cytolytic activity of CD8+ T cells. Notably, tumor-bearing mice infected with the parasite developed long-lasting and effective tumor-specific immunity. Consequently, we found that malaria parasite infection could enhance the immune response of lung cancer DNA vaccine pcDNA3.1-hMUC1 and the combination produced a synergistic antitumor effect. Conclusions/Significance Malaria infection significantly suppresses LLC growth via induction of innate and adaptive antitumor responses in a mouse model. These data suggest that the malaria parasite may provide a

  20. Antitumor immunization of mothers delays tumor development in cancer-prone offspring.

    Science.gov (United States)

    Barutello, Giuseppina; Curcio, Claudia; Spadaro, Michela; Arigoni, Maddalena; Trovato, Rosalinda; Bolli, Elisabetta; Zheng, Yujuan; Ria, Francesco; Quaglino, Elena; Iezzi, Manuela; Riccardo, Federica; Holmgren, Lars; Forni, Guido; Cavallo, Federica

    2015-05-01

    Maternal immunization is successfully applied against some life-threatening infectious diseases as it can protect the mother and her offspring through the passive transfer of maternal antibodies. Here, we sought to evaluate whether the concept of maternal immunization could also be applied to cancer immune-prevention. We have previously shown that antibodies induced by DNA vaccination against rat Her2 (neu) protect heterozygous neu-transgenic female (BALB-neuT) mice from autochthonous mammary tumor development. We, herein, seek to evaluate whether a similar maternal immunization can confer antitumor protection to BALB-neuT offspring. Significantly extended tumor-free survival was observed in BALB-neuT offspring born and fed by mothers vaccinated against neu, as compared to controls. Maternally derived anti-neu immunoglobulin G (IgG) was successfully transferred from mothers to newborns and was responsible for the protective effect. Vaccinated mothers and offspring also developed active immunity against neu as revealed by the presence of T-cell-mediated cytotoxicity against the neu immunodominant peptide. This active response was due to the milk transfer of immune complexes that were formed between the neu extracellular domain, shed from vaccine-transfected muscle cells, and the anti-neu IgG induced by the vaccine. These findings show that maternal immunization has the potential to hamper mammary cancer in genetically predestinated offspring and to develop into applications against lethal neonatal cancer diseases for which therapeutic options are currently unavailable.

  1. Decreased 7,12-dimethylbenz[a]anthracene-induced carcinogenesis coincides with the induction of antitumor immunities in adult female B6C3F1 mice pretreated with genistein.

    Science.gov (United States)

    Guo, Tai L; Chi, Rui P; Hernandez, Denise M; Auttachoat, Wimolnut; Zheng, Jian F

    2007-12-01

    The objective of this study was to determine if genistein (GEN) modulation of the immune responses might contribute to the increased host resistances to tumors. A time-course study was performed in adult female B6C3F1 mice that had been exposed to GEN for 1-4 weeks at the dose level of 20 mg/kg by gavage. A significant increase in ex vivo cytotoxic T lymphocyte (CTL) activity was observed in the periods of 2 weeks and 4 weeks. Moreover, increased activities of CTLs were associated with a decrease in the percentage of CD4(+)CD25(+) T cells and an increase in the production of interferon-gamma and activation of STAT1 (signal transducer and activator of transcription 1) and STAT4. Additionally, exposure of mice to GEN increased the activities of in vivo CTLs. An increased activity of natural killer (NK) cells was also observed. Further study in the B16F10 tumor model suggested that GEN-mediated enhancement in host resistance to B16F10 tumor was partially related to its potentiating effect on NK cells. Finally, 7,12-dimethylbenz[a]anthracene (DMBA)-induced tumor model was employed to determine the chemopreventive effect of oral GEN treatment. Mice pretreated with GEN for 2 weeks by gavage, the time when an enhanced CTL activity had been produced, had a decreased susceptibility toward DMBA-mediated carcinogenesis, while treatment with GEN after tumor induction conferred no protection. In conclusion, pretreatment with GEN by gavage could enhance host resistances to the B16F10 tumor and DMBA-induced carcinogenesis, suggesting that GEN modulation of immune response was, at least partially, responsible for the antitumor effect of this compound.

  2. Low-dose gemcitabine induces major histocompatibility complex class I-related chain A/B expression and enhances an antitumor innate immune response in pancreatic cancer.

    Science.gov (United States)

    Miyashita, Tomoharu; Miki, Kenji; Kamigaki, Takashi; Makino, Isamu; Nakagawara, Hisatoshi; Tajima, Hidehiro; Takamura, Hiroyuki; Kitagawa, Hirohisa; Fushida, Sachio; Ahmed, Ali K; Duncan, Mark D; Harmon, John W; Ohta, Tetsuo

    2017-02-01

    We investigated the effect of gemcitabine (GEM), a key drug for pancreatic cancer treatment, on the expression of cell surface MICA/B in pancreatic cancer cells and resulting cytotoxicity of γδ T cells. We assessed the effect of GEM on the upregulation of cell surface MICA/B expression by flow cytometry, utilizing six pancreatic cancer cell lines. MICA and CD16 expressions from resected pancreatic cancer patient specimens, which received neoadjuvant chemotherapy (NAC) with GEM, were analyzed by immunohistochemistry. GEM could increase MICA/B expression on cell surface in pancreatic cancer cell lines (in 2 of 6 cell lines). This effect was most effectively at concentration not affecting cell growth of GEM (0.001 μM), because MICA/B negative population was appeared at concentration at cytostatic and cytotoxic effect to cell growth (0.1 and 10 μM). The cytotoxic activity of γδ T cells against PANC-1 was detected and functions through interactions between NKG2D and MICA/B. However, the enhancement of NKG2D-dependent cytotoxicity with increased MICA/B expression, by GEM treatment, was not observed. In addition, soluble MIC molecules were released from pancreatic cancer cell lines in culture supernatant with GEM treatment. Immunohistochemical staining demonstrated that MICA expression in tumor cells and CD16 positive cells surrounding tumors were significantly higher in the NAC group compared to that of the control group. There was a significant correlation between NAC and MICA expression, as well as NAC and CD16 positive cell expression. The present results indicate that low-dose GEM-induced MICA/B expression enhances innate immune function rather than cytotoxicity in pancreatic cancer. In addition, our result suggests that the inhibition of cleavage and release of MIC molecules from the tumor surface could potentially improve NKG2D-dependent cytotoxicity.

  3. Irradiated tumor cells of lipopolysaccharide stimulation elicit an enhanced anti-tumor immunity.

    Science.gov (United States)

    Li, Yuli; Shen, Guobo; Nie, Wen; Li, Zhimian; Sang, Yaxiong; Zhang, Binglan; Wei, Yuquan

    2014-11-01

    Lipopolysaccharide (LPS) is a major component of the outer surface membrane of Gram-negative bacteria which has been proved an effective immune enhancer. Here, we investigated the anti-tumor effect of irradiated tumor cells that stimulated by LPS in mouse xenografts models. Tumor cells were irradiated after stimulation with 1 μg/mL LPS for 48 h. The C57BL/6 mice were immunized subcutaneously with irradiated tumor cells. The anti-tumor effect of lymphocytes of immunized mice was investigated. The cytotoxicity of spleen lymphocytes from immunized mice was determined by a standard (51)Cr-release assay. The roles of immune cell subsets in anti-tumor activity were assessed by injected intraperitoneally with monoclonal antibodies. We observed that the vaccine of irradiated tumor cell with LPS-stimulated elicited a stronger protective anti-tumor immunity than other controls. Adoptive transfer of lymphocytes of immunized mice showed that the cellular immune response was involved in the anti-tumor effect. And this effect was achieved by activation of antigen-specific CD8(+) T cell response and reduction of myeloid-derived suppressor cells (MDSCs, Gr1(+) CD11b (+) ), which were confirmed by depletion of immune cell subsets and flow cytometry analysis. In summary, our study showed that stimulation of LPS was able to enhance anti-tumor immunity of vaccination with tumor cells after irradiation treatment, which might be a new strategy for cancer therapy.

  4. Immune-Modulation by Epidermal Growth Factor Receptor Inhibitors: Implication on Anti-Tumor Immunity in Lung Cancer

    Science.gov (United States)

    Herrmann, Amanda C.; Bernatchez, Chantale; Haymaker, Cara; Molldrem, Jeffrey J.; Hong, Waun Ki; Perez-Soler, Roman

    2016-01-01

    Skin toxicity is the most common toxicity caused by Epidermal Growth Factor Receptor (EGFR) inhibitors, and has been associated with clinical efficacy. As EGFR inhibitors enhance the expression of antigen presenting molecules in affected skin keratinocytes, they may concurrently facilitate neo-antigen presentation in lung cancer tumor cells contributing to anti-tumor immunity. Here, we investigated the modulatory effect of the EGFR inhibitor, erlotinib on antigen presenting molecules and PD-L1, prominent immune checkpoint protein, of skin keratinocytes and lung cancer cell lines to delineate the link between EGFR signaling pathway inhibition and potential anti-tumor immunity. Erlotinib up-regulated MHC-I and MHC-II proteins on IFNγ treated keratinocytes but abrogated IFNγ-induced expression of PD-L1, suggesting the potential role of infiltrating autoreactive T cells in the damage of keratinocytes in affected skin. Interestingly, the surface expression of MHC-I, MHC-II, and PD-L1 was up-regulated in response to IFNγ more often in lung cancer cell lines sensitive to erlotinib, but only expression of PD-L1 was inhibited by erlotinib. Further, erlotinib significantly increased T cell mediated cytotoxicity on lung cancer cells. Lastly, the analysis of gene expression dataset of 186 lung cancer cell lines from Cancer Cell Line Encyclopedia demonstrated that overexpression of PD-L1 was associated with sensitivity to erlotinib and higher expression of genes related to antigen presenting pathways and IFNγ signaling pathway. Our findings suggest that the EGFR inhibitors can facilitate anti-tumor adaptive immune responses by breaking tolerance especially in EGFR driven lung cancer that are associated with overexpression of PD-L1 and genes related to antigen presentation and inflammation. PMID:27467256

  5. Immune-Modulation by Epidermal Growth Factor Receptor Inhibitors: Implication on Anti-Tumor Immunity in Lung Cancer.

    Directory of Open Access Journals (Sweden)

    Jin S Im

    Full Text Available Skin toxicity is the most common toxicity caused by Epidermal Growth Factor Receptor (EGFR inhibitors, and has been associated with clinical efficacy. As EGFR inhibitors enhance the expression of antigen presenting molecules in affected skin keratinocytes, they may concurrently facilitate neo-antigen presentation in lung cancer tumor cells contributing to anti-tumor immunity. Here, we investigated the modulatory effect of the EGFR inhibitor, erlotinib on antigen presenting molecules and PD-L1, prominent immune checkpoint protein, of skin keratinocytes and lung cancer cell lines to delineate the link between EGFR signaling pathway inhibition and potential anti-tumor immunity. Erlotinib up-regulated MHC-I and MHC-II proteins on IFNγ treated keratinocytes but abrogated IFNγ-induced expression of PD-L1, suggesting the potential role of infiltrating autoreactive T cells in the damage of keratinocytes in affected skin. Interestingly, the surface expression of MHC-I, MHC-II, and PD-L1 was up-regulated in response to IFNγ more often in lung cancer cell lines sensitive to erlotinib, but only expression of PD-L1 was inhibited by erlotinib. Further, erlotinib significantly increased T cell mediated cytotoxicity on lung cancer cells. Lastly, the analysis of gene expression dataset of 186 lung cancer cell lines from Cancer Cell Line Encyclopedia demonstrated that overexpression of PD-L1 was associated with sensitivity to erlotinib and higher expression of genes related to antigen presenting pathways and IFNγ signaling pathway. Our findings suggest that the EGFR inhibitors can facilitate anti-tumor adaptive immune responses by breaking tolerance especially in EGFR driven lung cancer that are associated with overexpression of PD-L1 and genes related to antigen presentation and inflammation.

  6. Augmentation of Antitumor Immunity by Human and Mouse CAR T Cells Secreting IL-18

    Directory of Open Access Journals (Sweden)

    Biliang Hu

    2017-09-01

    Full Text Available The effects of transgenically encoded human and mouse IL-18 on T cell proliferation and its application in boosting chimeric antigen receptor (CAR T cells are presented. Robust enhancement of proliferation of IL-18-secreting human T cells occurred in a xenograft model, and this was dependent on TCR and IL-18R signaling. IL-18 augmented IFN-γ secretion and proliferation of T cells activated by the endogenous TCR. TCR-deficient, human IL-18-expressing CD19 CAR T cells exhibited enhanced proliferation and antitumor activity in the xenograft model. Antigen-propelled activation of cytokine helper ensemble (APACHE CAR T cells displayed inducible expression of IL-18 and enhanced antitumor immunity. In an intact mouse tumor model, CD19-IL-18 CAR T cells induced deeper B cell aplasia, significantly enhanced CAR T cell proliferation, and effectively augmented antitumor effects in mice with B16F10 melanoma. These findings point to a strategy to develop universal CAR T cells for patients with solid tumors.

  7. Transfer of in vitro-expanded naïve T cells after lymphodepletion enhances antitumor immunity through the induction of polyclonal antitumor effector T cells.

    Directory of Open Access Journals (Sweden)

    Tomohiro Tanaka

    Full Text Available The adoptive transfer of effector T cells combined with lymphodepletion has demonstrated promising antitumor effects in mice and humans, although the availability of tumor-specific T cells is limited. We and others have also demonstrated that the transfer of polyclonal naïve T cells induces tumor-specific effector T cells and enhances antitumor immunity after lymphodepletion. Because tumors have been demonstrated to induce immunosuppressive networks and regulate the function of T cells, obtaining a sufficient number of fully functional naïve T cells that are able to differentiate into tumor-specific effector T cells remains difficult. To establish culture methods to obtain a large number of polyclonal T cells that are capable of differentiating into tumor-specific effector T cells, naïve T cells were activated with anti-CD3 mAbs in vitro. These cells were stimulated with IL-2 and IL-7 for the CD8 subset or with IL-7 and IL-23 for the CD4 subset. Transfer of these hyperexpanded T cells after lymphodepletion showed significant antitumor efficacy, and tumor-specific effector T cells were primed from these expanded T cells in tumor-bearing hosts. Moreover, these ex vivo-expanded T cells maintained T cell receptor diversity and showed long-term persistence of memory against specific tumors. Further analyses revealed that combination therapy consisting of vaccination with dendritic cells that were co-cultured with irradiated whole tumor cells and the transfer of ex vivo-expanded T cells significantly enhanced antitumor immunity. These results indicate that the transfer of ex vivo-expanded polyclonal T cells can be combined with other immunotherapies and augment antitumor effects.

  8. Anti-tumor immune response after photodynamic therapy

    Science.gov (United States)

    Mroz, Pawel; Castano, Ana P.; Wu, Mei X.; Kung, Andrew L.; Hamblin, Michael R.

    2009-06-01

    Anti-tumor immunity is stimulated after PDT due a number of factors including: the acute inflammatory response caused by PDT, release of antigens from PDT-damaged tumor cells, priming of the adaptive immune system to recognize tumor-associated antigens (TAA), and induction of heat-shock proteins. The induction of specific CD8+ T-lymphocyte cells that recognize major histocompatibility complex class I (MHC-I) restricted epitopes of TAAs is a highly desirable goal in cancer therapy as it would allow the treatment of tumors that may have already metastasized. The PDT killed tumor cells may be phagocytosed by dendritic cells (DC) that then migrate to draining lymph nodes and prime naÃve T-cells that recognize TAA epitopes. We have carried out in vivo PDT with a BPD-mediated vascular regimen using a pair of BALB/c mouse colon carcinomas: CT26 wild type expressing the naturally occurring retroviral antigen gp70 and CT26.CL25 additionally expressing beta-galactosidase (b-gal) as a model tumor rejection antigen. PDT of CT26.CL25 cured 100% of tumors but none of the CT26WT tumors (all recurred). Cured CT26.CL25 mice were resistant to rechallenge. Moreover mice with two bilateral CT26.CL25 tumors that had only one treated with PDT demonstrated spontaneous regression of 70% of untreated contralateral tumors. T-lymphocytes were isolated from lymph nodes of PDT cured mice that recognized a particular peptide specific to b-gal antigen. T-lymphocytes from LN were able to kill CT26.CL25 target cells in vitro but not CT26WT cells as shown by a chromium release assay. CT26.CL25 tumors treated with PDT and removed five days later had higher levels of Th1 cytokines than CT26 WT tumors showing a higher level of immune response. When mice bearing CT26WT tumors were treated with a regimen of low dose cyclophosphamide (CY) 2 days before, PDT led to 100% of cures (versus 0% without CY) and resistance to rechallenge. Low dose CY is thought to deplete regulatory T-cells (Treg, CD4+CD25+foxp

  9. LV305, a dendritic cell-targeting integration-deficient ZVex(TM)-based lentiviral vector encoding NY-ESO-1, induces potent anti-tumor immune response.

    Science.gov (United States)

    Albershardt, Tina Chang; Campbell, David James; Parsons, Andrea Jean; Slough, Megan Merrill; Ter Meulen, Jan; Berglund, Peter

    2016-01-01

    We have engineered an integration-deficient lentiviral vector, LV305, to deliver the tumor antigen NY-ESO-1 to human dendritic cells in vivo through pseudotyping with a modified Sindbis virus envelop protein. Mice immunized once with LV305 developed strong, dose-dependent, multifunctional, and cytotoxic NY-ESO-1-specific cluster of differentiation 8 (CD8) T cells within 14 days post-immunization and could be boosted with LV305 at least twice to recall peak-level CD8 T-cell responses. Immunization with LV305 protected mice against tumor growth in an NY-ESO-1-expressing CT26 lung metastasis model, with the protective effect abrogated upon depletion of CD8 T cells. Adoptive transfer of CD8 T cells, alone or together with CD4 T cells or natural killer cells, from LV305-immunized donor mice to tumor-bearing recipient mice conferred significant protection against metastatic tumor growth. Biodistribution of injected LV305 in mice was limited to the site of injection and the draining lymph node, and injected LV305 exhibited minimal excretion. Mice injected with LV305 developed little to no adverse effects, as evaluated by toxicology studies adherent to good laboratory practices. Taken together, these data support the development of LV305 as a clinical candidate for treatment against tumors expressing NY-ESO-1.

  10. LV305, a dendritic cell-targeting integration-deficient ZVexTM-based lentiviral vector encoding NY-ESO-1, induces potent anti-tumor immune response

    Science.gov (United States)

    Albershardt, Tina Chang; Campbell, David James; Parsons, Andrea Jean; Slough, Megan Merrill; ter Meulen, Jan; Berglund, Peter

    2016-01-01

    We have engineered an integration-deficient lentiviral vector, LV305, to deliver the tumor antigen NY-ESO-1 to human dendritic cells in vivo through pseudotyping with a modified Sindbis virus envelop protein. Mice immunized once with LV305 developed strong, dose-dependent, multifunctional, and cytotoxic NY-ESO-1-specific cluster of differentiation 8 (CD8) T cells within 14 days post-immunization and could be boosted with LV305 at least twice to recall peak-level CD8 T-cell responses. Immunization with LV305 protected mice against tumor growth in an NY-ESO-1-expressing CT26 lung metastasis model, with the protective effect abrogated upon depletion of CD8 T cells. Adoptive transfer of CD8 T cells, alone or together with CD4 T cells or natural killer cells, from LV305-immunized donor mice to tumor-bearing recipient mice conferred significant protection against metastatic tumor growth. Biodistribution of injected LV305 in mice was limited to the site of injection and the draining lymph node, and injected LV305 exhibited minimal excretion. Mice injected with LV305 developed little to no adverse effects, as evaluated by toxicology studies adherent to good laboratory practices. Taken together, these data support the development of LV305 as a clinical candidate for treatment against tumors expressing NY-ESO-1. PMID:27626061

  11. Suppression of Antitumor Immune Responses by Human Papillomavirus through Epigenetic Downregulation of CXCL14

    Directory of Open Access Journals (Sweden)

    Louis Cicchini

    2016-05-01

    Full Text Available High-risk human papillomaviruses (HPVs are causally associated with multiple human cancers. Previous studies have shown that the HPV oncoprotein E7 induces immune suppression; however, the underlying mechanisms remain unknown. To understand the mechanisms by which HPV deregulates host immune responses in the tumor microenvironment, we analyzed gene expression changes of all known chemokines and their receptors using our global gene expression data sets from human HPV-positive and -negative head/neck cancer and cervical tissue specimens in different disease stages. We report that, while many proinflammatory chemokines increase expression throughout cancer progression, CXCL14 is dramatically downregulated in HPV-positive cancers. HPV suppression of CXCL14 is dependent on E7 and associated with DNA hypermethylation in the CXCL14 promoter. Using in vivo mouse models, we revealed that restoration of Cxcl14 expression in HPV-positive mouse oropharyngeal carcinoma cells clears tumors in immunocompetent syngeneic mice, but not in Rag1-deficient mice. Further, Cxcl14 reexpression significantly increases natural killer (NK, CD4+ T, and CD8+ T cell infiltration into the tumor-draining lymph nodes in vivo. In vitro transwell migration assays show that Cxcl14 reexpression induces chemotaxis of NK, CD4+ T, and CD8+ T cells. These results suggest that CXCL14 downregulation by HPV plays an important role in suppression of antitumor immune responses. Our findings provide a new mechanistic understanding of virus-induced immune evasion that contributes to cancer progression.

  12. Histone Deacetylase Inhibitor AR-42 Enhances E7-Specific CD8+ T Cell-Mediated Antitumor Immunity Induced by Therapeutic HPV DNA Vaccination

    OpenAIRE

    Lee, Sung Yong; Huang, Zhuomin; Kang, Tae Heung; Soong, Ruey-Shyang; Knoff, Jayne; Axenfeld, Ellen; Wang, Chenguang; Alvarez, Ronald D.; Chen, Ching-Shih; Hung, Chien-Fu; Wu, T.-C.

    2013-01-01

    We have previously created a potent DNA vaccine encoding calreticulin linked to the HPV oncogenic protein E7 (CRT/E7). While treatment of the CRT/E7 DNA vaccine generates significant tumor-specific immune responses in vaccinated mice, the potency of the DNA vaccine could potentially be improved by co-administration of a histone deacetylase inhibitor (HDACi) as HDACi have been shown to increase the expression of MHC class I and II molecules. Thus, we aimed to determine whether co-administratio...

  13. Breast cancer vaccines delivered by dendritic cell-targeted lentivectors induce potent antitumor immune responses and protect mice from mammary tumor growth.

    Science.gov (United States)

    Bryson, Paul D; Han, Xiaolu; Truong, Norman; Wang, Pin

    2017-10-13

    Breast cancer immunotherapy is a potent treatment option, with antibody therapies such as trastuzumab increasing 2-year survival rates by 50%. However, active immunotherapy through vaccination has generally been clinically ineffective. One potential means of improving vaccine therapy is by delivering breast cancer antigens to dendritic cells (DCs) for enhanced antigen presentation. To accomplish this in vivo, we pseudotyped lentiviral vector (LV) vaccines with a modified Sindbis Virus glycoprotein so that they could deliver genes encoding the breast cancer antigen alpha-lactalbumin (Lalba) or erb-b2 receptor tyrosine kinase 2 (ERBB2 or HER2) directly to resident DCs. We hypothesized that utilizing these DC-targeting lentiviral vectors asa breast cancer vaccine could lead to an improved immune response against self-antigens found in breast cancer tumors. Indeed, single injections of the vaccine vectors were able to amplify antigen-specific CD8T cells 4-6-fold over naïve mice, similar to the best published vaccine regimens. Immunization of these mice completely inhibited tumor growth in a foreign antigen environment (LV-ERBB2 in wildtype mice), and it reduced the rate of tumor growth in a self-antigen environment (LV-Lalba in wildtype or LV-ERBB2 in MMTV-huHER2 transgenic). These results show that a single injection with targeted lentiviral vectors can be an effective immunotherapy for breast cancer. Furthermore, they could be combined with other immunotherapeutic regimens to improve outcomes for patients with breast cancer. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. Photodynamic therapy stimulates anti-tumor immunity in a murine mastocytoma model

    Science.gov (United States)

    Mroz, Pawel; Hamblin, Michael R.

    2008-02-01

    Photodynamic therapy (PDT) involves the IV administration of photosensitizers followed by illumination of the tumor with red light producing reactive oxygen species that eventually cause vascular shutdown and tumor cell apoptosis. Anti-tumor immunity is stimulated after PDT due to the acute inflammatory response, recognition of tumor-specific antigens, and induction of heat-shock proteins, while the three commonest cancer therapies (surgery, chemotherapy and radiotherapy) all tend to suppress the immune system. Like many other immunotherapies, the extent of the immune response after PDT tends to depend on the antigenicity of the particular tumor, or in other words, whether the tumor contains proteins with the correct characteristics to provide peptides that can bind to MHC class I molecules and provide a target for cytolytic T lymphocytes. We have described certain mouse tumors containing defined or naturally occurring tumor associated antigens that respond particularly well to PDT, and potent immune responses capable of destroying distant untreated tumors can be induced. In this report we address the induction of immunity after PDT of the DBA2 mastocytoma known as P815. This tumor was the first mouse tumor to be shown to possess a tumor-rejection antigen capable of being recognized by cytotoxic T-cells.

  15. Neem leaf glycoprotein promotes dual generation of central and effector memory CD8(+) T cells against sarcoma antigen vaccine to induce protective anti-tumor immunity.

    Science.gov (United States)

    Ghosh, Sarbari; Sarkar, Madhurima; Ghosh, Tithi; Guha, Ipsita; Bhuniya, Avishek; Saha, Akata; Dasgupta, Shayani; Barik, Subhasis; Bose, Anamika; Baral, Rathindranath

    2016-03-01

    We have previously shown that Neem Leaf Glycoprotein (NLGP) mediates sustained tumor protection by activating host immune response. Now we report that adjuvant help from NLGP predominantly generates CD44(+)CD62L(high)CCR7(high) central memory (TCM; in lymph node) and CD44(+)CD62L(low)CCR7(low) effector memory (TEM; in spleen) CD8(+) T cells of Swiss mice after vaccination with sarcoma antigen (SarAg). Generated TCM and TEM participated either to replenish memory cell pool for sustained disease free states or in rapid tumor eradication respectively. TCM generated after SarAg+NLGP vaccination underwent significant proliferation and IL-2 secretion following SarAg re-stimulation. Furthermore, SarAg+NLGP vaccination helps in greater survival of the memory precursor effector cells at the peak of the effector response and their maintenance as mature memory cells, in comparison to single modality treatment. Such response is corroborated with the reduced phosphorylation of FOXO in the cytosol and increased KLF2 in the nucleus associated with enhanced CD62L, CCR7 expression of lymph node-resident CD8(+) T cells. However, spleen-resident CD8(+) T memory cells show superior efficacy for immediate memory-to-effector cell conversion. The data support in all aspects that SarAg+NLGP demonstrate superiority than SarAg vaccination alone that benefits the host by rapid effector functions whenever required, whereas, central-memory cells are thought to replenish the memory cell pool for ultimate sustained disease free survival till 60 days following post-vaccination tumor inoculation. Copyright © 2016 Elsevier Ltd. All rights reserved.

  16. The Pig as a Large Animal Model for Studying Anti-Tumor Immune Responses

    DEFF Research Database (Denmark)

    Overgaard, Nana Haahr

    The immune system plays a crucial role in cancer development and progression. Cancer immunoediting encompasses three phases: elimination, equilibrium, and escape; together, describing the complex interplay between tumor and immune cells. Specifically, the immune system both protects against cancer...... of autologous tumor cells, underlining the capacity of the Oncopig immune system to mount a cytotoxic anti-tumor response. Using the results from RNA-seq analysis, we propose a potential mechanism for in vivo inhibition of anti-tumor cytotoxicity based on elevated expression of the immunosuppressive genes IDO1...... support that the Oncopig provides a crucial platform for studying anti-tumor immune responses in a large in vivo system, although the model currently only allows preclinical testing of therapeutics against the early stages of cancer....

  17. FOXP3+ Treg as a therapeutic target for promoting anti-tumor immunity.

    Science.gov (United States)

    Whiteside, Theresa L

    2018-04-01

    Regulatory T cells (Treg) characterized by expression of FOXP3 and strong immunosuppressive activity play a key role in regulating homeostasis in health and disease. Areas covered: Human Treg are highly diverse phenotypically and functionally. In the tumor microenvironment (TME), Treg are reprogrammed by the tumor, acquiring an activated phenotype and enhanced suppressor functions. No unique phenotypic markers for Treg accumulating in human tumors exist. Treg are heterogeneous and use numerous mechanisms to mediate suppression, which either silences anti-tumor immune surveillance or prevents tissue damage by activated T cells. Treg plasticity in the TME endows them with dual functionality. Treg frequency in tumors associates either with poor or improved survival. Treg responses to immune checkpoint inhibition (ICI) differ from the restorative effects ICIs induce in other immune cells. Therapies used to silence Treg, including ICIs, are only partly successful. Treg persistence and resistance to depletion are critical for maintaining homeostasis. Expert opinion: Treg emerge as a heterogeneous subset of immunosuppressive T cells, which usually, but not always, favor tumor progression. Treg are also engaged in non-immune activities that benefit the host. Therapeutic silencing of Treg in cancer requires a deeper understanding of Treg activities in human health and disease.

  18. Recombinant protein rMBP-NAP restricts tumor progression by triggering antitumor immunity in mouse metastatic lung cancer.

    Science.gov (United States)

    Wang, Ting; Du, Mingxuan; Ji, Zhenyu; Ding, Cong; Wang, Chengbo; Men, Yingli; Liu, Shimeng; Liang, Taotao; Liu, Xin; Kang, Qiaozhen

    2018-02-01

    Recombinant Helicobacter pylori neutrophil-activating protein fused with maltose-binding protein (rMBP-NAP), a potential TLR2 ligand, was reported to possess immunomodulatory effects on in situ tumors in our previous study. In the present work, we attempt to elucidate the effect of rMBP-NAP at the local immune modulation in B16-F10-induced metastatic lung cancer. Our results demonstrated that growth of B16-F10 melanoma metastases in the lung was significantly arrested after rMBP-NAP treatment, along with marked reduction in metastatic lung nodules and significant increase in survival. The treatment induced both local and systemic immune responses, which were associated with higher influx of CD4 + /CD8 + T cells and drove toward Th1-like and cytotoxic immune environment. Moreover, rMBP-NAP also showed significant anti-angiogenic activity by reducing vascularization in lung tumor sections. rMBP-NAP could induce antitumor immunity through activating Th1 cells and producing pro-inflammatory cytokines, which are responsible for the effective cytotoxic immune response against cancer progression. Our findings indicate that rMBP-NAP might be a novel antitumor therapeutic strategy.

  19. Tumor-altered dendritic cell function: implications for anti-tumor immunity

    Directory of Open Access Journals (Sweden)

    Kristian Michael Hargadon

    2013-07-01

    Full Text Available Dendritic cells are key regulators of both innate and adaptive immunity, and the array of immunoregulatory functions exhibited by these cells is dictated by their differentiation, maturation, and activation status. Although a major role for these cells in the induction of immunity to pathogens has long been appreciated, data accumulated over the last several years has demonstrated that DC are also critical regulators of anti-tumor immune responses. However, despite the potential for stimulation of robust anti-tumor immunity by DC, tumor-altered DC function has been observed in many cancer patients and tumor-bearing animals and is often associated with tumor immune escape. Such dysfunction has significant implications for both the induction of natural anti-tumor immune responses as well as the efficacy of immunotherapeutic strategies that target endogenous DC in situ or that employ exogenous DC as part of anti-cancer immunization maneuvers. In this review, the major types of tumor-altered DC function will be described, with emphasis on recent insights into the mechanistic bases for the inhibition of DC differentiation from hematopoietic precursors, the altered programming of DC precursors to differentiate into myeloid-derived suppressor cells or tumor-associated macrophages, the suppression of DC maturation and activation, and the induction of immunoregulatory DC by tumors, tumor-derived factors, and tumor-associated cells within the milieu of the tumor microenvironment. The impact of these tumor-altered cells on the quality of the overall anti-tumor immune response will also be discussed. Finally, this review will also highlight questions concerning tumor-altered DC function that remain unanswered, and it will address factors that have limited advances in the study of this phenomenon in order to focus future research efforts in the field on identifying strategies for interfering with tumor-associated DC dysfunction and improving DC-mediated anti-tumor

  20. Tumor-altered dendritic cell function: implications for anti-tumor immunity.

    Science.gov (United States)

    Hargadon, Kristian M

    2013-01-01

    Dendritic cells (DC) are key regulators of both innate and adaptive immunity, and the array of immunoregulatory functions exhibited by these cells is dictated by their differentiation, maturation, and activation status. Although a major role for these cells in the induction of immunity to pathogens has long been appreciated, data accumulated over the last several years has demonstrated that DC are also critical regulators of anti-tumor immune responses. However, despite the potential for stimulation of robust anti-tumor immunity by DC, tumor-altered DC function has been observed in many cancer patients and tumor-bearing animals and is often associated with tumor immune escape. Such dysfunction has significant implications for both the induction of natural anti-tumor immune responses as well as the efficacy of immunotherapeutic strategies that target endogenous DC in situ or that employ exogenous DC as part of anti-cancer immunization maneuvers. In this review, the major types of tumor-altered DC function will be described, with emphasis on recent insights into the mechanistic bases for the inhibition of DC differentiation from hematopoietic precursors, the altered programing of DC precursors to differentiate into myeloid-derived suppressor cells or tumor-associated macrophages, the suppression of DC maturation and activation, and the induction of immunoregulatory DC by tumors, tumor-derived factors, and tumor-associated cells within the milieu of the tumor microenvironment. The impact of these tumor-altered cells on the quality of the overall anti-tumor immune response will also be discussed. Finally, this review will also highlight questions concerning tumor-altered DC function that remain unanswered, and it will address factors that have limited advances in the study of this phenomenon in order to focus future research efforts in the field on identifying strategies for interfering with tumor-associated DC dysfunction and improving DC-mediated anti-tumor immunity.

  1. Regulation of CD8+T Cells and Antitumor Immunity by Notch Signaling.

    Science.gov (United States)

    Tsukumo, Shin-Ichi; Yasutomo, Koji

    2018-01-01

    Cancer immunosurveillance is critical for the elimination of neoplastic cells. In addition, recent advances in immunological checkpoint blockade drugs have revealed the importance of the immune system in cancer treatment. As a component of the immune system, CD8 + T cells have important roles in suppressing tumors. CD8 + T cells can kill tumor cells with cytotoxic molecules, such as granzymes and perforin. IFNγ, which is produced by CD8 + T cells, can increase the expression of MHC class I antigens by tumor cells, thereby rendering them better targets for CD8 + T cells. IFNγ also has crucial functions in enhancing the antitumor abilities of other immune cells. Therefore, it has been hypothesized that antitumor immunity could be improved by modulating the activity of CD8 + T cells. The Notch pathway regulates CD8 + T cells in multiple ways. It directly upregulates mRNA expression of granzyme B and perforin, enhances differentiation toward short-lived effector cells, and maintains memory T cells. Intriguingly, CD8 + T cell-specific Notch2 deletion impairs antitumor immunity, whereas the stimulation of the Notch pathway can increase tumor suppression. In this review, we will summarize the roles of the Notch pathway in CD8 + T cells and discuss issues and implications for its use in antitumor immunity.

  2. Combination therapy with local radiofrequency ablation and systemic vaccine enhances antitumor immunity and mediates local and distal tumor regression.

    Directory of Open Access Journals (Sweden)

    Sofia R Gameiro

    Full Text Available PURPOSE: Radiofrequency ablation (RFA is a minimally invasive energy delivery technique increasingly used for focal therapy to eradicate localized disease. RFA-induced tumor-cell necrosis generates an immunogenic source of tumor antigens known to induce antitumor immune responses. However, RFA-induced antitumor immunity is insufficient to control metastatic progression. We sought to characterize (a the role of RFA dose on immunogenic modulation of tumor and generation of immune responses and (b the potential synergy between vaccine immunotherapy and RFA aimed at local tumor control and decreased systemic progression. EXPERIMENTAL DESIGN: Murine colon carcinoma cells expressing the tumor-associated (TAA carcinoembryonic antigen (CEA (MC38-CEA(+ were studied to examine the effect of sublethal hyperthermia in vitro on the cells' phenotype and sensitivity to CTL-mediated killing. The effect of RFA dose was investigated in vivo impacting (a the phenotype and growth of MC38-CEA(+ tumors and (b the induction of tumor-specific immune responses. Finally, the molecular signature was evaluated as well as the potential synergy between RFA and poxviral vaccines expressing CEA and a TRIad of COstimulatory Molecules (CEA/TRICOM. RESULTS: In vitro, sublethal hyperthermia of MC38-CEA(+ cells (a increased cell-surface expression of CEA, Fas, and MHC class I molecules and (b rendered tumor cells more susceptible to CTL-mediated lysis. In vivo, RFA induced (a immunogenic modulation on the surface of tumor cells and (b increased T-cell responses to CEA and additional TAAs. Combination therapy with RFA and vaccine in CEA-transgenic mice induced a synergistic increase in CD4(+ T-cell immune responses to CEA and eradicated both primary CEA(+ and distal CEA(- s.c. tumors. Sequential administration of low-dose and high-dose RFA with vaccine decreased tumor recurrence compared to RFA alone. These studies suggest a potential clinical benefit in combining RFA with vaccine

  3. Effect of Paris saponin on antitumor and immune function in U14 ...

    African Journals Online (AJOL)

    bearing mice, and reduced the serum IL-4 level. The Paris saponin can inhibit U14 cell growth and prolong survival time of mice; it is speculated that the Paris saponin may express its anti-tumor activity by improving the body's immune system.

  4. Activation of Anti-tumor Immune Response by Ablation of HCC with Nanosecond Pulsed Electric Field.

    Science.gov (United States)

    Xu, Xiaobo; Chen, Yiling; Zhang, Ruiqing; Miao, Xudong; Chen, Xinhua

    2018-03-28

    Locoregional therapy is playing an increasingly important role in the non-surgical management of hepatocellular carcinoma (HCC). The novel technique of non-thermal electric ablation by nanosecond pulsed electric field has been recognized as a potential locoregional methodology for indicated HCC. This manuscript explores the most recent studies to indicate its unique anti-tumor immune response. The possible immune mechanism, termed as nano-pulse stimulation, was also analyzed.

  5. Homeostatic T Cell Expansion to Induce Anti-Tumor Autoimmunity in Breast Cancer

    National Research Council Canada - National Science Library

    Baccala, Roberto

    2007-01-01

    ... that (a) homeostatic T-cell proliferation consistently elicits anti-tumor responses; (b) irradiation is more effective than Tcell depletion by antibodies in inducing anti-tumor responses mediated by homeostatic T-cell proliferation...

  6. The influence of physical activity in the anti-tumor immune response in experimental breast tumor.

    Science.gov (United States)

    Bianco, Thiago M; Abdalla, Douglas R; Desidério, Chamberttan S; Thys, Sofie; Simoens, Cindy; Bogers, John-Paul; Murta, Eddie F C; Michelin, Márcia A

    2017-10-01

    This study aimed to investigate the influence of physical activity in innate immunity to conduce to an effective antitumoral immune response analyzing the phenotype and activation status of infiltrating cells. We analysed the intracellular cytokines and the transcription factors of tumor infiltrating lymphocytes (TILS) and spleen leukocytes. The Nos2 gene expression was evaluated in spleen cells and futhermore the ROS production was measured and spleen cells; another cell evaluated was dendritic cells (TIDCs), their cytokines expression and membrane molecules; finally to understood the results obtained, we analysed the dendritic cells obtained from bone marrow. Were used female Balb/c mice divided into 4 groups: two controls without tumor, sedentary (GI) and trained (GII) and two groups with tumor, sedentary (GIII) or trained (GIV). The physical activity (PA) was realized acoording swimming protocol. Tumor was induced by injection of 4T1 cells. All experiments were performed in biological triplicate. After the experimental period, the tumor was removed and the cells were identified by flow cytometry with labeling to CD4, CD8, CD11c, CD11b, CD80, CD86 and Ia, and intracelular staining IL-10, IL-12, TNF-α, IFN-γ, IL-17, Tbet, GATA3, RORγt and FoxP3. The bone marrow of the animals was obtained to analyse the derivated DCs by flow cytometry and culture cells to obtain the supernatant to measure the cytokines. Our results demonstrated that the PA inhibit the tumoral growth although not to change the number of TILS, but reduced expression of GATA-3, ROR-γT, related with poor prognosis, and TNF-α intracellular; however occur one significantly reduction in TIDCS, but these cells expressed more co-stimulatory and presentation molecules. Furthermore, we observed that the induced PA stimulated the gene expression of Tbet and the production of inflammatory cytokines suggesting an increase of Th1 systemic response. The results evaluating the systemic influence in DCs

  7. Linalool Exhibits Cytotoxic Effects by Activating Antitumor Immunity

    Directory of Open Access Journals (Sweden)

    Mei-Yin Chang

    2014-05-01

    Full Text Available According to recent studies, the Plantaginaceae, which are traditional Chinese herbal remedies, have potential for use in viral infection treatment and cancer therapy. Linalool and p-coumaric acid are two of the biologically active compounds that can be isolated from the Plantaginaceae. This study mainly focused on investigating the bioactivity of linalool as well as the bioactivity of p-coumaric acid in terms of their cytotoxic effects on cancer cells. Whether the mechanisms of such effects are generated through apoptosis and immunoregulatory activity were also investigated. By using WST-1 analysis, it was shown that linalool and p-coumaric acid have good inhibitory effects against breast, colorectal and liver cancer cells. The IC50 values of linalool for those cancer cell types were 224 μM, 222 μM, and 290 μM, respectively, and the IC50 values of p-coumaric acid were 693 μM, 215 μM and 87 μM, respectively. Cell cycle analysis also confirmed that linalool and p-coumaric acid can lead to apoptosis. By using flow cytometry, it was determined that treatment with linalool rather than p-coumaric acid significantly increased the sub-G1 phase and that there were more cells concentrated in the G1 phase. Furthermore, by using cytokine array analysis, we found that linalool can stimulate IFN-γ, IL-13, IL-2, IL-21, IL-21R, IL-4, IL-6sR and TNF-α secretion. This demonstrated that in addition to the bidirectional regulation capabilities found in linalool, it also induces Th1 cellular immune response in T-47D cells. These results showed that linalool holds great potential for use in cancer therapy, and we believe that it could provide an alternative way to take action against tumors.

  8. Linalool exhibits cytotoxic effects by activating antitumor immunity.

    Science.gov (United States)

    Chang, Mei-Yin; Shen, Yi-Ling

    2014-05-22

    According to recent studies, the Plantaginaceae, which are traditional Chinese herbal remedies, have potential for use in viral infection treatment and cancer therapy. Linalool and p-coumaric acid are two of the biologically active compounds that can be isolated from the Plantaginaceae. This study mainly focused on investigating the bioactivity of linalool as well as the bioactivity of p-coumaric acid in terms of their cytotoxic effects on cancer cells. Whether the mechanisms of such effects are generated through apoptosis and immunoregulatory activity were also investigated. By using WST-1 analysis, it was shown that linalool and p-coumaric acid have good inhibitory effects against breast, colorectal and liver cancer cells. The IC50 values of linalool for those cancer cell types were 224 μM, 222 μM, and 290 μM, respectively, and the IC50 values of p-coumaric acid were 693 μM, 215 μM and 87 μM, respectively. Cell cycle analysis also confirmed that linalool and p-coumaric acid can lead to apoptosis. By using flow cytometry, it was determined that treatment with linalool rather than p-coumaric acid significantly increased the sub-G1 phase and that there were more cells concentrated in the G1 phase. Furthermore, by using cytokine array analysis, we found that linalool can stimulate IFN-γ, IL-13, IL-2, IL-21, IL-21R, IL-4, IL-6sR and TNF-α secretion. This demonstrated that in addition to the bidirectional regulation capabilities found in linalool, it also induces Th1 cellular immune response in T-47D cells. These results showed that linalool holds great potential for use in cancer therapy, and we believe that it could provide an alternative way to take action against tumors.

  9. IgE/FcεRI-Mediated Antigen Cross-Presentation by Dendritic Cells Enhances Anti-Tumor Immune Responses

    Directory of Open Access Journals (Sweden)

    Barbara Platzer

    2015-03-01

    Full Text Available Epidemiologic studies discovered an inverse association between immunoglobulin E (IgE-mediated allergies and cancer, implying tumor-protective properties of IgE. However, the underlying immunologic mechanisms remain poorly understood. Antigen cross-presentation by dendritic cells (DCs is of key importance for anti-tumor immunity because it induces the generation of cytotoxic CD8+ T lymphocytes (CTLs with specificity for tumor antigens. We demonstrate that DCs use IgE and FcεRI, the high-affinity IgE receptor, for cross-presentation and priming of CTLs in response to free soluble antigen at low doses. Importantly, IgE/FcεRI-mediated cross-presentation is a distinct receptor-mediated pathway because it does not require MyD88 signals or IL-12 induction in DCs. Using passive immunization with tumor antigen-specific IgE and DC-based vaccination experiments, we demonstrate that IgE-mediated cross-presentation significantly improves anti-tumor immunity and induces memory responses in vivo. Our findings suggest a cellular mechanism for the tumor-protective features of IgE and expand the known physiological functions of this immunoglobulin.

  10. Reprogramming antitumor immunity against chemoresistant ovarian cancer by a CXCR4 antagonist-armed viral oncotherapy

    Directory of Open Access Journals (Sweden)

    Marcin P Komorowski

    2016-01-01

    Full Text Available Ovarian cancer remains the most lethal gynecologic malignancy owing to late detection, intrinsic and acquired chemoresistance, and remarkable heterogeneity. Here, we explored approaches to inhibit metastatic growth of murine and human ovarian tumor variants resistant to paclitaxel and carboplatin by oncolytic vaccinia virus expressing a CXCR4 antagonist to target the CXCL12 chemokine/CXCR4 receptor signaling axis alone or in combination with doxorubicin. The resistant variants exhibited augmented expression of the hyaluronan receptor CD44 and CXCR4 along with elevated Akt and ERK1/2 activation and displayed an increased susceptibility to viral infection compared with the parental counterparts. The infected cultures were more sensitive to doxorubicin-mediated killing both in vitro and in tumor-challenged mice. Mechanistically, the combination treatment increased apoptosis and phagocytosis of tumor material by dendritic cells associated with induction of antitumor immunity. Targeting syngeneic tumors with this regimen increased intratumoral infiltration of antitumor CD8+ T cells. This was further enhanced by reducing the immunosuppressive network by the virally-delivered CXCR4 antagonist, which augmented antitumor immune responses and led to tumor-free survival. Our results define novel strategies for treatment of drug-resistant ovarian cancer that increase immunogenic cell death and reverse the immunosuppressive tumor microenvironment, culminating in antitumor immune responses that control metastatic tumor growth.

  11. Positive and negative influence of the matrix architecture on antitumor immune surveillance.

    Science.gov (United States)

    Peranzoni, Elisa; Rivas-Caicedo, Ana; Bougherara, Houcine; Salmon, Hélène; Donnadieu, Emmanuel

    2013-12-01

    The migration of T cells and access to tumor antigens is of utmost importance for the induction of protective anti-tumor immunity. Once having entered a malignant site, T cells encounter a complex environment composed of non-tumor cells along with the extracellular matrix (ECM). It is now well accepted that a deregulated ECM favors tumor progression and metastasis. Recent progress in imaging technologies has also highlighted the impact of the matrix architecture found in solid tumor on immune cells and especially T cells. In this review, we argue that the ability of T cells to mount an antitumor response is dependent on the matrix structure, more precisely on the balance between pro-migratory reticular fiber networks and unfavorable migration zones composed of dense and aligned ECM structures. Thus, the matrix architecture, that has long been considered to merely provide the structural framework of connective tissues, can play a key role in facilitating or suppressing the antitumor immune surveillance. A new challenge in cancer therapy will be to develop approaches aimed at altering the architecture of the tumor stroma, rendering it more permissive to antitumor T cells.

  12. Epistasis between MicroRNAs 155 and 146a during T Cell-Mediated Antitumor Immunity

    Directory of Open Access Journals (Sweden)

    Thomas B. Huffaker

    2012-12-01

    Full Text Available An increased understanding of antitumor immunity is necessary for improving cell-based immunotherapies against human cancers. Here, we investigated the roles of two immune system-expressed microRNAs (miRNAs, miR-155 and miR-146a, in the regulation of antitumor immune responses. Our results indicate that miR-155 promotes and miR-146a inhibits interferon γ (IFNγ responses by T cells and reduces solid tumor growth in vivo. Using a double-knockout (DKO mouse strain deficient in both miR-155 and miR-146a, we have also identified an epistatic relationship between these two miRNAs. DKO mice had defective T cell responses and tumor growth phenotypes similar to miR-155−/− mice. Further analysis of the T cell compartment revealed that miR-155 modulates IFNγ expression through a mechanism involving repression of Ship1. Our work reveals critical roles for miRNAs in the reciprocal regulation of CD4+ and CD8+ T cell-mediated antitumor immunity and demonstrates the dominant nature of miR-155 during its promotion of immune responses.

  13. Activation of antitumor immune responses by Ganoderma formosanum polysaccharides in tumor-bearing mice.

    Science.gov (United States)

    Wang, Cheng-Li; Lu, Chiu-Ying; Hsueh, Ying-Chao; Liu, Wen-Hsiung; Chen, Chun-Jen

    2014-11-01

    Fungi of the genus Ganoderma are basidiomycetes that have been used as traditional medicine in Asia and have been shown to exhibit various pharmacological activities. We recently found that PS-F2, a polysaccharide fraction purified from the submerged culture broth of Ganoderma formosanum, stimulates the maturation of dendritic cells and primes a T helper 1 (Th1)-polarized adaptive immune response in vivo. In this study, we investigated whether the immune adjuvant function of PS-F2 can stimulate antitumor immune responses in tumor-bearing mice. Continuous intraperitoneal or oral administration of PS-F2 effectively suppressed the growth of colon 26 (C26) adenocarcinoma, B16 melanoma, and sarcoma 180 (S180) tumor cells in mice without adverse effects on the animals' health. PS-F2 did not cause direct cytotoxicity on tumor cells, and it lost the antitumor effect in mice with severe combined immunodeficiency (SCID). CD4(+) T cells, CD8(+) T cells, and serum from PS-F2-treated tumor-bearing mice all exhibited antitumor activities when adoptively transferred to naïve animals, indicating that PS-F2 treatment stimulates tumor-specific cellular and humoral immune responses. These data demonstrate that continuous administration of G. formosanum polysaccharide PS-F2 can activate host immune responses against ongoing tumor growth, suggesting that PS-F2 can potentially be developed into a preventive/therapeutic agent for cancer immunotherapy.

  14. Effector, Memory, and Dysfunctional CD8+ T Cell Fates in the Antitumor Immune Response

    Science.gov (United States)

    2016-01-01

    The adaptive immune system plays a pivotal role in the host's ability to mount an effective, antigen-specific immune response against tumors. CD8+ tumor-infiltrating lymphocytes (TILs) mediate tumor rejection through recognition of tumor antigens and direct killing of transformed cells. In growing tumors, TILs are often functionally impaired as a result of interaction with, or signals from, transformed cells and the tumor microenvironment. These interactions and signals can lead to transcriptional, functional, and phenotypic changes in TILs that diminish the host's ability to eradicate the tumor. In addition to effector and memory CD8+ T cells, populations described as exhausted, anergic, senescent, and regulatory CD8+ T cells have been observed in clinical and basic studies of antitumor immune responses. In the context of antitumor immunity, these CD8+ T cell subsets remain poorly characterized in terms of fate-specific biomarkers and transcription factor profiles. Here we discuss the current characterization of CD8+ T cell fates in antitumor immune responses and discuss recent insights into how signals in the tumor microenvironment influence TIL transcriptional networks to promote CD8+ T cell dysfunction. PMID:27314056

  15. [Functions of eosinophil granulocytes: from anti-parasite immunity to anti-tumoral potential].

    Science.gov (United States)

    Capron, Monique; Legrand, Fanny

    2009-02-01

    Eosinophils have long been considered simply as effectors of adaptive immune responses during parasitic infections and inflammatory processes. Their role in allergic manifestations and mucosal responses is mediated by membrane receptors that allow them to interact with IgE and IgA antibodies. The recent demonstration that human eosinophils express innate immune receptors suggests that they may also play a role in antitumoral immune surveillance. Experimental evidence shows that human eosinophils have tumoricidal potential, in synergy with other effector cells, notably by releasing cytotoxic molecules.

  16. Radiotherapy and antitumor immunity. An immunomodifying effect of ionizing radiation

    International Nuclear Information System (INIS)

    Klimovich, V.B.

    1983-01-01

    It has been found that a tumor is formed and spread under the influence of opposite but not mutually exlusive immune reactions. Radiation effect along with direct injury of tumoral cells and feeding neoplasms vessels changes the established equilibrium of immunologic factors, therefore it should be considered as immunomodifying one. The wide spread opinion according to which the therapeutic effect in case of radiotherapy is attained despite its depressive effect on immunity, should be revised as not corresponding to the facts. The data available allow one to assume that immunologic factors may play an essential role in realization of therapeutic effect of irradiation as well as in limitation of its efficiency. Investigations into immunologic aspects of oncology and radiology should be therefore directed to the search of methods of control of immune reactions of organism - the tumor bearer. This may discover considerable reserves of increasing radiotherapeutic efficiency

  17. Regulatory T cells as suppressors of anti-tumor immunity: Role of metabolism.

    Science.gov (United States)

    De Rosa, Veronica; Di Rella, Francesca; Di Giacomo, Antonio; Matarese, Giuseppe

    2017-06-01

    Novel concepts in immunometabolism support the hypothesis that glucose consumption is also used to modulate anti-tumor immune responses, favoring growth and expansion of specific cellular subsets defined in the past as suppressor T cells and currently reborn as regulatory T (Treg) cells. During the 1920s, Otto Warburg and colleagues observed that tumors consumed high amounts of glucose compared to normal tissues, even in the presence of oxygen and completely functioning mitochondria. However, the role of the Warburg Effect is still not completely understood, particularly in the context of an ongoing anti-tumor immune response. Current experimental evidence suggests that tumor-derived metabolic restrictions can drive T cell hyporesponsiveness and immune tolerance. For example, several glycolytic enzymes, deregulated in cancer, contribute to tumor progression independently from their canonical metabolic activity. Indeed, they can control apoptosis, gene expression and activation of specific intracellular pathways, thus suggesting a direct link between metabolic switches and pro-tumorigenic transcriptional programs. Focus of this review is to define the specific metabolic pathways controlling Treg cell immunobiology in the context of anti-tumor immunity and tumor progression. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. A TLR9 agonist enhances the anti-tumor immunity of peptide and lipopeptide vaccines via different mechanisms.

    Science.gov (United States)

    Song, Ying-Chyi; Liu, Shih-Jen

    2015-07-28

    The toll-like receptor 9 (TLR9) agonists CpG oligodeoxynucleotides (CpG ODNs) have been recognized as promising adjuvants for vaccines against infectious diseases and cancer. However, the role of TLR9 signaling in the regulation of antigen uptake and presentation is not well understood. Therefore, to investigate the effects of TLR9 signaling, this study used synthetic peptides (IDG) and lipopeptides (lipoIDG), which are internalized by dendritic cells (DCs) via endocytosis-dependent and endocytosis-independent pathways, respectively. Our data demonstrated that the internalization of lipoIDG and IDG by bone marrow-derived dendritic cells (BMDCs) was not enhanced in the presence of CpG ODNs; however, CpG ODNs prolonged the co-localization of IDG with CpG ODNs in early endosomes. Surprisingly, CpG ODNs enhanced CD8(+) T cell responses, and the anti-tumor effects of IDG immunization were stronger than those of lipoIDG immunization. LipoIDG admixed with CpG ODNs induced low levels of CD8(+) T cells and partially inhibit tumor growth. Our findings suggest that CpG ODNs increase the retention of antigens in early endosomes, which is important for eliciting anti-tumor immunity. These results will facilitate the application of CpG adjuvants in the design of different vaccines.

  19. Reprogramming Antitumor Immune Responses with microRNAs

    Science.gov (United States)

    2013-10-01

    disseminate throughout the peritoneal cavity. For tumor cells, ascites provides an ideal milieu to detach and seed distally. Furthermore, crucial...these responses were able to put tumors in check for relatively prolonged periods. However, after this latency period, tumors started to grow very...then, overwhelming experimental evidence demonstrates that both the innate and adaptive immune systems play a non-redundant role in the prevention or

  20. Bridging Innate and Adaptive Antitumor Immunity Targeting Glycans

    Directory of Open Access Journals (Sweden)

    Anastas Pashov

    2010-01-01

    Full Text Available Effective immunotherapy for cancer depends on cellular responses to tumor antigens. The role of major histocompatibility complex (MHC in T-cell recognition and T-cell receptor repertoire selection has become a central tenet in immunology. Structurally, this does not contradict earlier findings that T-cells can differentiate between small hapten structures like simple glycans. Understanding T-cell recognition of antigens as defined genetically by MHC and combinatorially by T cell receptors led to the “altered self” hypothesis. This notion reflects a more fundamental principle underlying immune surveillance and integrating evolutionarily and mechanistically diverse elements of the immune system. Danger associated molecular patterns, including those generated by glycan remodeling, represent an instance of altered self. A prominent example is the modification of the tumor-associated antigen MUC1. Similar examples emphasize glycan reactivity patterns of antigen receptors as a phenomenon bridging innate and adaptive but also humoral and cellular immunity and providing templates for immunotherapies.

  1. CDK4/6 Inhibition Augments Antitumor Immunity by Enhancing T-cell Activation.

    Science.gov (United States)

    Deng, Jiehui; Wang, Eric S; Jenkins, Russell W; Li, Shuai; Dries, Ruben; Yates, Kathleen; Chhabra, Sandeep; Huang, Wei; Liu, Hongye; Aref, Amir R; Ivanova, Elena; Paweletz, Cloud P; Bowden, Michaela; Zhou, Chensheng W; Herter-Sprie, Grit S; Sorrentino, Jessica A; Bisi, John E; Lizotte, Patrick H; Merlino, Ashley A; Quinn, Max M; Bufe, Lauren E; Yang, Annan; Zhang, Yanxi; Zhang, Hua; Gao, Peng; Chen, Ting; Cavanaugh, Megan E; Rode, Amanda J; Haines, Eric; Roberts, Patrick J; Strum, Jay C; Richards, William G; Lorch, Jochen H; Parangi, Sareh; Gunda, Viswanath; Boland, Genevieve M; Bueno, Raphael; Palakurthi, Sangeetha; Freeman, Gordon J; Ritz, Jerome; Haining, W Nicholas; Sharpless, Norman E; Arthanari, Haribabu; Shapiro, Geoffrey I; Barbie, David A; Gray, Nathanael S; Wong, Kwok-Kin

    2018-02-01

    Immune checkpoint blockade, exemplified by antibodies targeting the PD-1 receptor, can induce durable tumor regressions in some patients. To enhance the efficacy of existing immunotherapies, we screened for small molecules capable of increasing the activity of T cells suppressed by PD-1. Here, we show that short-term exposure to small-molecule inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) significantly enhances T-cell activation, contributing to antitumor effects in vivo , due in part to the derepression of NFAT family proteins and their target genes, critical regulators of T-cell function. Although CDK4/6 inhibitors decrease T-cell proliferation, they increase tumor infiltration and activation of effector T cells. Moreover, CDK4/6 inhibition augments the response to PD-1 blockade in a novel ex vivo organotypic tumor spheroid culture system and in multiple in vivo murine syngeneic models, thereby providing a rationale for combining CDK4/6 inhibitors and immunotherapies. Significance: Our results define previously unrecognized immunomodulatory functions of CDK4/6 and suggest that combining CDK4/6 inhibitors with immune checkpoint blockade may increase treatment efficacy in patients. Furthermore, our study highlights the critical importance of identifying complementary strategies to improve the efficacy of immunotherapy for patients with cancer. Cancer Discov; 8(2); 216-33. ©2017 AACR. See related commentary by Balko and Sosman, p. 143 See related article by Jenkins et al., p. 196 This article is highlighted in the In This Issue feature, p. 127 . ©2017 American Association for Cancer Research.

  2. Fluorescent nanodiamonds engage innate immune effector cells: A potential vehicle for targeted anti-tumor immunotherapy.

    Science.gov (United States)

    Suarez-Kelly, Lorena P; Campbell, Amanda R; Rampersaud, Isaac V; Bumb, Ambika; Wang, Min S; Butchar, Jonathan P; Tridandapani, Susheela; Yu, Lianbo; Rampersaud, Arfaan A; Carson, William E

    2017-04-01

    Fluorescent nanodiamonds (FNDs) are nontoxic, infinitely photostable, and emit fluorescence in the near infrared region. Natural killer (NK) cells and monocytes are part of the innate immune system and are crucial to the control of carcinogenesis. FND-mediated stimulation of these cells may serve as a strategy to enhance anti-tumor activity. FNDs were fabricated with a diameter of 70±28 nm. Innate immune cell FND uptake, viability, surface marker expression, and cytokine production were evaluated in vitro. Evaluation of fluorescence emission from the FNDs was conducted in an animal model. In vitro results demonstrated that treatment of immune cells with FNDs resulted in significant dose-dependent FND uptake, no compromise in cell viability, and immune cell activation. FNDs were visualized in an animal model. Hence, FNDs may serve as novel agents with "track and trace" capabilities to stimulate innate immune cell anti-tumor responses, especially as FNDs are amenable to surface-conjugation with immunomodulatory molecules. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. An evolutionary perspective on anti-tumor immunity

    Directory of Open Access Journals (Sweden)

    David John Klinke

    2013-01-01

    Full Text Available The challenges associated with demonstrating a durable response using molecular targeted therapies in cancer has sparked a renewed interest in viewing cancer from an evolutionary perspective. Evolutionary processes have three common traits: heterogeneity, dynamics, and a selective fitness landscape. Mutagens randomly alter the genome of host cells creating a population of cells that contain different somatic mutations. This genomic rearrangement perturbs cellular homeostasis through changing how cells interact with their tissue microenvironment. To counterbalance the ability of mutated cells to outcompete for limited resources, control structures are encoded within the cell and within the organ system, such as innate and adaptive immunity, to restore cellular homeostasis. These control structures shape the selective fitness landscape and determine whether a cell that harbors particular somatic mutations is retained or eliminated from a cell population. While next-generation sequencing has revealed the complexity and heterogeneity of oncogenic transformation, understanding the dynamics of oncogenesis and how cancer cells alter the selective fitness landscape remain unclear. In this technology review, we will summarize how recent advances in technology have impacted our understanding of these three attributes of cancer as an evolutionary process. In particular, we will focus on how advances in genome sequencing have enabled quantifying cellular heterogeneity, advances in computational power have enabled explicit testing of postulated intra- and intercellular control structures against the available data using simulation, and advances in proteomics have enabled identifying novel mechanisms of cellular cross-talk that cancer cells use to alter the fitness landscape.

  4. Mechanical disruption of tumors by iron particles and magnetic field application results in increased anti-tumor immune responses.

    Directory of Open Access Journals (Sweden)

    Myriam N Bouchlaka

    Full Text Available The primary tumor represents a potential source of antigens for priming immune responses for disseminated disease. Current means of debulking tumors involves the use of cytoreductive conditioning that impairs immune cells or removal by surgery. We hypothesized that activation of the immune system could occur through the localized release of tumor antigens and induction of tumor death due to physical disruption of tumor architecture and destruction of the primary tumor in situ. This was accomplished by intratumor injection of magneto-rheological fluid (MRF consisting of iron microparticles, in Balb/c mice bearing orthotopic 4T1 breast cancer, followed by local application of a magnetic field resulting in immediate coalescence of the particles, tumor cell death, slower growth of primary tumors as well as decreased tumor progression in distant sites and metastatic spread. This treatment was associated with increased activation of DCs in the draining lymph nodes and recruitment of both DCs and CD8(+T cells to the tumor. The particles remained within the tumor and no toxicities were observed. The immune induction observed was significantly greater compared to cryoablation. Further anti-tumor effects were observed when MRF/magnet therapy was combined with systemic low dose immunotherapy. Thus, mechanical disruption of the primary tumor with MRF/magnetic field application represents a novel means to induce systemic immune activation in cancer.

  5. Viral subversion of APOBEC3s: Lessons for anti-tumor immunity and tumor immunotherapy.

    Science.gov (United States)

    Borzooee, Faezeh; Asgharpour, Mahdi; Quinlan, Emma; Grant, Michael D; Larijani, Mani

    2017-12-06

    APOBEC3s (A3) are endogenous DNA-editing enzymes that are expressed in immune cells including T lymphocytes. A3s target and mutate the genomes of retroviruses that infect immune tissues such as the human immunodeficiency virus (HIV). Therefore, A3s were classically defined as host anti-viral innate immune factors. In contrast, we and others showed that A3s can also benefit the virus by mediating escape from adaptive immune recognition and drugs. Crucially, whether A3-mediated mutations help or hinder HIV, is not up to chance. Rather, the virus has evolved multiple mechanisms to actively and maximally subvert A3 activity. More recently, extensive A3 mutational footprints in tumor genomes have been observed in many different cancers. This suggests a role for A3s in cancer initiation and progression. On the other hand, multiple anti-tumor activities of A3s have also come to light, including impact on immune checkpoint molecules and possible generation of tumor neo-antigens. Here, we review the studies that reshaped the view of A3s from anti-viral innate immune agents to host factors exploited by HIV to escape from immune recognition. Viruses and tumors share many attributes, including rapid evolution and adeptness at exploiting mutations. Given this parallel, we then discuss the pro- and anti-tumor roles of A3s, and suggest that lessons learned from studying A3s in the context of anti-viral immunity can be applied to tumor immunotherapy.

  6. Tertiary Lymphoid Structures in Cancer: Drivers of Antitumor Immunity, Immunosuppression, or Bystander Sentinels in Disease?

    Science.gov (United States)

    Colbeck, Emily Jayne; Ager, Ann; Gallimore, Awen; Jones, Gareth Wyn

    2017-01-01

    Secondary lymphoid organs are integral to initiation and execution of adaptive immune responses. These organs provide a setting for interactions between antigen-specific lymphocytes and antigen-presenting cells recruited from local infected or inflamed tissues. Secondary lymphoid organs develop as a part of a genetically preprogrammed process during embryogenesis. However, organogenesis of secondary lymphoid tissues can also be recapitulated in adulthood during de novo lymphoid neogenesis of tertiary lymphoid structures (TLSs). These ectopic lymphoid-like structures form in the inflamed tissues afflicted by various pathological conditions, including cancer, autoimmunity, infection, or allograft rejection. Studies are beginning to shed light on the function of such structures in different disease settings, raising important questions regarding their contribution to progression or resolution of disease. Data show an association between the tumor-associated TLSs and a favorable prognosis in various types of human cancer, attracting the speculation that TLSs support effective local antitumor immune responses. However, definitive evidence for the role for TLSs in fostering immune responses in vivo are lacking, with current data remaining largely correlative by nature. In fact, some more recent studies have even demonstrated an immunosuppressive, tumor-promoting role for cancer-associated TLSs. In this review, we will discuss what is known about the development of cancer-associated TLSs and the current understanding of their potential role in the antitumor immune response. PMID:29312327

  7. Nanotechnology based therapeutic modality to boost anti-tumor immunity and collapse tumor defense.

    Science.gov (United States)

    Hu, Xiaomeng; Wu, Tingting; Bao, Yuling; Zhang, Zhiping

    2017-06-28

    Cancer is still the leading cause of death. While traditional treatments such as surgery, chemotherapy and radiotherapy play dominating roles, recent breakthroughs in cancer immunotherapy indicate that the influence of immune system on cancer development is virtually beyond our expectation. Manipulating the immune system to fight against cancer has been thriving in recent years. Further understanding of tumor anatomy provides opportunities to put a brake on immunosuppression by overcoming tumor intrinsic resistance or modulating tumor microenvironment. Nanotechnology which provides versatile engineered approaches to enhance therapeutic effects may potentially contribute to the development of future cancer treatment modality. In this review, we will focus on the application of nanotechnology both in boosting anti-tumor immunity and collapsing tumor defense. Copyright © 2017. Published by Elsevier B.V.

  8. Up-regulation of GITRL on dendritic cells by WGP improves anti-tumor immunity in murine Lewis lung carcinoma.

    Directory of Open Access Journals (Sweden)

    Jie Tian

    Full Text Available BACKGROUND: β-Glucans have been shown to function as a potent immunomodulator to stimulate innate and adaptive immune responses, which contributes to their anti-tumor property. However, their mechanisms of action are still elusive. Glucocorticoid-induced TNF receptor ligand (GITRL, a member of the TNF superfamily, binds to its receptor, GITR, on both effector and regulatory T cells, generates a positive co-stimulatory signal implicated in a wide range of T cell functions, which is important for the development of immune responses. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we found that whole β-glucan particles (WGPs could activate dendritic cells (DCs via dectin-1 receptor, and increase the expression of GITRL on DCs in vitro and in vivo. Furthermore, we demonstrated that the increased GITRL on DCs could impair the regulartory T cell (Treg-mediated suppression and enhance effector T cell proliferation in a GITR/GITRL dependent way. In tumor models, DCs with high levels of GITRL were of great potential to prime cytotoxic T lymphocyte (CTL responses and down-regulate the suppressive activity of Treg cells, thereby leading to the delayed tumor progression. CONCLUSIONS/SIGNIFICANCE: These findings suggest that particulate β-glucans can be used as an immunomodulator to stimulate potent T cell-mediated adaptive immunity while down-regulate suppressive immune activity via GITR/GITRL interaction, leading to a more efficient defense mechanism against tumor development.

  9. Autophagy: an adaptive metabolic response to stress shaping the antitumor immunity.

    Science.gov (United States)

    Viry, Elodie; Paggetti, Jerome; Baginska, Joanna; Mgrditchian, Takouhie; Berchem, Guy; Moussay, Etienne; Janji, Bassam

    2014-11-01

    Several environmental-associated stress conditions, including hypoxia, starvation, oxidative stress, fast growth and cell death suppression, modulate both cellular metabolism and autophagy to enable cancer cells to rapidly adapt to environmental stressors, maintain proliferation and evade therapies. It is now widely accepted that autophagy is essential to support cancer cell growth and metabolism and that metabolic reprogramming in cancer can also favor autophagy induction. Therefore, this complex interplay between autophagy and tumor cell metabolism will provide unique opportunities to identify new therapeutic targets. As the regulation of the autophagic activity is related to metabolism, it is important to elucidate the exact molecular mechanism which drives it and the functional consequence of its activation in the context of cancer therapy. In this review, we will summarize the role of autophagy in shaping the cellular response to an abnormal tumor microenvironment and discuss some recent results on the molecular mechanism by which autophagy plays such a role in the context of the anti-tumor immune response. We will also describe how autophagy activation can behave as a double-edged sword, by activating the immune response in some circumstances, and impairing the anti-tumor immunity in others. These findings imply that defining the precise context-specific role for autophagy in cancer is critical to guide autophagy-based therapeutics which are becoming key strategies to overcome tumor resistance to therapies. Copyright © 2014 Elsevier Inc. All rights reserved.

  10. Secretion of Rhoptry and Dense Granule Effector Proteins by Nonreplicating Toxoplasma gondii Uracil Auxotrophs Controls the Development of Antitumor Immunity

    Science.gov (United States)

    Fox, Barbara A.; Sanders, Kiah L.; Rommereim, Leah M.; Bzik, David J.

    2016-01-01

    Nonreplicating type I uracil auxotrophic mutants of Toxoplasma gondii possess a potent ability to activate therapeutic immunity to established solid tumors by reversing immune suppression in the tumor microenvironment. Here we engineered targeted deletions of parasite secreted effector proteins using a genetically tractable Δku80 vaccine strain to show that the secretion of specific rhoptry (ROP) and dense granule (GRA) proteins by uracil auxotrophic mutants of T. gondii in conjunction with host cell invasion activates antitumor immunity through host responses involving CD8α+ dendritic cells, the IL-12/interferon-gamma (IFN-γ) TH1 axis, as well as CD4+ and CD8+ T cells. Deletion of parasitophorous vacuole membrane (PVM) associated proteins ROP5, ROP17, ROP18, ROP35 or ROP38, intravacuolar network associated dense granule proteins GRA2 or GRA12, and GRA24 which traffics past the PVM to the host cell nucleus severely abrogated the antitumor response. In contrast, deletion of other secreted effector molecules such as GRA15, GRA16, or ROP16 that manipulate host cell signaling and transcriptional pathways, or deletion of PVM associated ROP21 or GRA3 molecules did not affect the antitumor activity. Association of ROP18 with the PVM was found to be essential for the development of the antitumor responses. Surprisingly, the ROP18 kinase activity required for resistance to IFN-γ activated host innate immunity related GTPases and virulence was not essential for the antitumor response. These data show that PVM functions of parasite secreted effector molecules, including ROP18, manipulate host cell responses through ROP18 kinase virulence independent mechanisms to activate potent antitumor responses. Our results demonstrate that PVM associated rhoptry effector proteins secreted prior to host cell invasion and dense granule effector proteins localized to the intravacuolar network and host nucleus that are secreted after host cell invasion coordinately control the

  11. Protective antitumor activity induced by a fusion vaccine with murine ...

    African Journals Online (AJOL)

    Targeting angiogenesis is an effective strategy for anticancer therapy. The vascular endothelialcadherin (VE-cad) regulated angiogenesis is a potential target for anti-angiogenesis. Here, we develop a fusion vaccine plasmid DNA pSec-MBD2-VE-cad from VE-cad and murine beta defensin2 (MBD2) to induce immunity for ...

  12. Adenosine can thwart antitumor immune responses elicited by radiotherapy. Therapeutic strategies alleviating protumor ADO activities

    Energy Technology Data Exchange (ETDEWEB)

    Vaupel, Peter [Klinikum rechts der Isar, Technische Universitaet Muenchen (TUM), Department of Radiation Oncology, Munich (Germany); Multhoff, Gabriele [Klinikum rechts der Isar, Technische Universitaet Muenchen (TUM), Department of Radiation Oncology, Munich (Germany); Helmholtz Zentrum Muenchen, Institute for innovative Radiotherapy (iRT), Experimental Immune Biology, Neuherberg (Germany)

    2016-05-15

    By studying the bioenergetic status we could show that the development of tumor hypoxia is accompanied, apart from myriad other biologically relevant effects, by a substantial accumulation of adenosine (ADO). ADO has been shown to act as a strong immunosuppressive agent in tumors by modulating the innate and adaptive immune system. In contrast to ADO, standard radiotherapy (RT) can either stimulate or abrogate antitumor immune responses. Herein, we present ADO-mediated mechanisms that may thwart antitumor immune responses elicited by RT. An overview of the generation, accumulation, and ADO-related multifaceted inhibition of immune functions, contrasted with the antitumor immune effects of RT, is provided. Upon hypoxic stress, cancer cells release ATP into the extracellular space where nucleotides are converted into ADO by hypoxia-sensitive, membrane-bound ectoenzymes (CD39/CD73). ADO actions are mediated upon binding to surface receptors, mainly A2A receptors on tumor and immune cells. Receptor activation leads to a broad spectrum of strong immunosuppressive properties facilitating tumor escape from immune control. Mechanisms include (1) impaired activity of CD4 + T and CD8 + T, NK cells and dendritic cells (DC), decreased production of immuno-stimulatory lymphokines, and (2) activation of Treg cells, expansion of MDSCs, promotion of M2 macrophages, and increased activity of major immunosuppressive cytokines. In addition, ADO can directly stimulate tumor proliferation and angiogenesis. ADO mechanisms described can thwart antitumor immune responses elicited by RT. Therapeutic strategies alleviating tumor-promoting activities of ADO include respiratory hyperoxia or mild hyperthermia, inhibition of CD39/CD73 ectoenzymes or blockade of A2A receptors, and inhibition of ATP-release channels or ADO transporters. (orig.) [German] Untersuchungen des bioenergetischen Status ergaben, dass Tumorhypoxie neben vielen anderen bedeutsamen biologischen Effekten zu einem starken

  13. Effector Regulatory T Cells Reflect the Equilibrium between Antitumor Immunity and Autoimmunity in Adult T-cell Leukemia.

    Science.gov (United States)

    Ureshino, Hiroshi; Shindo, Takero; Nishikawa, Hiroyoshi; Watanabe, Nobukazu; Watanabe, Eri; Satoh, Natsuko; Kitaura, Kazutaka; Kitamura, Hiroaki; Doi, Kazuko; Nagase, Kotaro; Kimura, Hiromi; Samukawa, Makoto; Kusunoki, Susumu; Miyahara, Masaharu; Shin-I, Tadasu; Suzuki, Ryuji; Sakaguchi, Shimon; Kimura, Shinya

    2016-08-01

    The regulatory T cells (Treg) with the most potent immunosuppressive activity are the effector Tregs (eTreg) with a CD45RA(-)Foxp3(++)CCR4(+) phenotype. Adult T-cell leukemia (ATL) cells often share the Treg phenotype and also express CCR4. Although mogamulizumab, a monoclonal antibody to CCR4, shows marked antitumor effects against ATL and peripheral T-cell lymphoma, concerns have been raised that it may induce severe autoimmune immunopathology by depleting eTregs. Here, we present case reports for two patients with ATL who responded to mogamulizumab but developed a severe skin rash and autoimmune brainstem encephalitis. Deep sequencing of the T-cell receptor revealed that ATL cells and naturally occurring Tregs within the cell population with a Treg phenotype can be clearly distinguished according to CADM1 expression. The onset of skin rash and brainstem encephalitis was coincident with eTreg depletion from the peripheral blood, whereas ATL relapses were coincident with eTreg recovery. These results imply that eTreg numbers in the peripheral blood sensitively reflect the equilibrium between antitumor immunity and autoimmunity, and that mogamulizumab might suppress ATL until the eTreg population recovers. Close monitoring of eTreg numbers is crucial if we are to provide immunomodulatory treatments that target malignancy without severe adverse events. Cancer Immunol Res; 4(8); 644-9. ©2016 AACR. ©2016 American Association for Cancer Research.

  14. Interleukin-17 acts as double-edged sword in anti-tumor immunity and tumorigenesis.

    Science.gov (United States)

    Qian, Xin; Chen, Hankui; Wu, Xiaofeng; Hu, Ling; Huang, Qi; Jin, Yang

    2017-01-01

    Interleukin-17 (IL-17), a proinflammatory cytokine, mainly produced by Th17 cells, participates in both innate and adaptive immune responses and is involved in various diseases, including infectious diseases, autoimmune disorders and cancer. Emerging evidence indicates that IL-17 not only has an oncogenic role in tumorigenesis by regulating tumor angiogenesis and enhancing tumor immune evasion but also exerts anti-tumor functions by enhancing natural killer (NK) cells and cytotoxic T lymphocytes (CTLs) activation and through the recruitment of neutrophils, NK cells and CD4 + and CD8 + T cells to tumor tissue. In this review, we provide an overview on the basic biology of IL-17 and recent findings regarding its enigmatic double-edged features in tumorigenesis, with special attention to the roles of IL-17 produced by tumor cells interacting with other factors in the tumor microenvironment. Copyright © 2015 Elsevier Ltd. All rights reserved.

  15. Clinical development of reovirus for cancer therapy: An oncolytic virus with immune-mediated antitumor activity.

    Science.gov (United States)

    Gong, Jun; Sachdev, Esha; Mita, Alain C; Mita, Monica M

    2016-03-26

    Reovirus is a double-stranded RNA virus with demonstrated oncolysis or preferential replication in cancer cells. The oncolytic properties of reovirus appear to be dependent, in part, on activated Ras signaling. In addition, Ras-transformation promotes reovirus oncolysis by affecting several steps of the viral life cycle. Reovirus-mediated immune responses can present barriers to tumor targeting, serve protective functions against reovirus systemic toxicity, and contribute to therapeutic efficacy through antitumor immune-mediated effects via innate and adaptive responses. Preclinical studies have demonstrated the broad anticancer activity of wild-type, unmodified type 3 Dearing strain reovirus (Reolysin(®)) across a spectrum of malignancies. The development of reovirus as an anticancer agent and available clinical data reported from 22 clinical trials will be reviewed.

  16. Antitumor and immune regulation activities of the extracts of some Chinese marine invertebrates

    Science.gov (United States)

    Zhang, Lixin; Fan, Xiao; Han, Lijun

    2005-03-01

    Extracts of 21 marine invertebrates belonging to Coelenterata, Mollusca, Annelida, Bryozoa, Echiura, Arthropoda, Echinodermata and Urochordata were screened for the studies on their antitumor and immune regulation activities. Antitumor activity was determined by MTT method and immune regulation activity was studied using T- and B-lymphocytes in mice spleen in vitro. It was found that the n-butanol part of Asterina pectinifera, the acetic ether part of Tubuaria marina, 95% ethanol extract of Acanthochiton rubrolineatus have a high inhibition rate of 96.7%, 63.9% and 50.5% respectively on tumor cell line HL-60 at the concentration of 0.063 mg/ml. The inhibition rate of the acetic ether part of Tubuaria marina on the tumor cell line A-549 is 65.4% at concentration of 0.063 mg/mL. The 95% ethanol extract of Meretrix meretrix has so outstanding promoting effect on T-lymphocytes that their multiplication increases 25% when the sample concentration is only 1 μg/ml. On B-lymphocytes, the 95% extract of Rapana venosa, at concentration of 100 μg/ml, has a promotion percentage of 60%. On the other hand, under the condition of no cytotoxic effect, the 95% ethanol extracts of Acanthochiton rubrolineatus and Cellana toreum can reach 92% inhibition rate on T lymphocyte at concentration of 100 μg/ml, while the inhibition rate on B lymphocyte of the 95% extract of Acanthochiton rubrolineatus reaches 92% at the same concentration.

  17. Antitumor Immunity Produced by the Liver Kupffer Cells, NK Cells, NKT Cells, and CD8+ CD122+ T Cells

    Directory of Open Access Journals (Sweden)

    Shuhji Seki

    2011-01-01

    Full Text Available Mouse and human livers contain innate immune leukocytes, NK cells, NKT cells, and macrophage-lineage Kupffer cells. Various bacterial components, including Toll-like receptor (TLR ligands and an NKT cell ligand (α-galactocylceramide, activate liver Kupffer cells, which produce IL-1, IL-6, IL-12, and TNF. IL-12 activates hepatic NK cells and NKT cells to produce IFN-γ, which further activates hepatic T cells, in turn activating phagocytosis and cytokine production by Kupffer cells in a positive feedback loop. These immunological events are essentially evoked to protect the host from bacterial and viral infections; however, these events also contribute to antitumor and antimetastatic immunity in the liver by activated liver NK cells and NKT cells. Bystander CD8+CD122+ T cells, and tumor-specific memory CD8+T cells, are also induced in the liver by α-galactocylceramide. Furthermore, adoptive transfer experiments have revealed that activated liver lymphocytes may migrate to other organs to inhibit tumor growth, such as the lungs and kidneys. The immunological mechanism underlying the development of hepatocellular carcinoma in cirrhotic livers in hepatitis C patients and liver innate immunity as a double-edged sword (hepatocyte injury/regeneration, septic shock, autoimmune disease, etc. are also discussed.

  18. CCL3 Enhances Antitumor Immune Priming in the Lymph NodeviaIFNγ with Dependency on Natural Killer Cells.

    Science.gov (United States)

    Allen, Frederick; Rauhe, Peter; Askew, David; Tong, Alexander A; Nthale, Joseph; Eid, Saada; Myers, Jay T; Tong, Caryn; Huang, Alex Y

    2017-01-01

    Lymph node (LN) plays a critical role in tumor cell survival outside of the primary tumor sites and dictates overall clinical response in many tumor types (1, 2). Previously, we and others have demonstrated that CCL3 plays an essential role in orchestrating T cell-antigen-presenting cell (APC) encounters in the draining LN following vaccination, and such interactions enhance the magnitude of the memory T cell pool (3-5). In the current study, we investigate the cellular responses in the tumor-draining lymph nodes (TDLNs) of a CCL3-secreting CT26 colon tumor (L3TU) as compared to wild-type tumor (WTTU) during the priming phase of an antitumor response (≤10 days). In comparison to WTTU, inoculation of L3TU resulted in suppressed tumor growth, a phenomenon that is accompanied by altered in vivo inflammatory responses on several fronts. Autologous tumor-derived CCL3 (aCCL3) secretion by L3TU bolstered the recruitment of T- and B-lymphocytes, tissue-migratory CD103 + dendritic cells (DCs), and CD49b + natural killer (NK) cells, resulting in significant increases in the differentiation and activation of multiple Interferon-gamma (IFNγ)-producing leukocytes in the TDLN. During this early phase of immune priming, NK cells constitute the major producers of IFNγ in the TDLN. CCL3 also enhances CD8+ T cell proliferation and differentiation by augmenting DC capacity to drive T cell activation in the TDLN. Our results revealed that CCL3-dependent IFNγ production and CCL3-induced DC maturation drive the priming of effective antitumor immunity in the TDLN.

  19. CCL3 Enhances Antitumor Immune Priming in the Lymph Node via IFNγ with Dependency on Natural Killer Cells

    Directory of Open Access Journals (Sweden)

    Frederick Allen

    2017-10-01

    Full Text Available Lymph node (LN plays a critical role in tumor cell survival outside of the primary tumor sites and dictates overall clinical response in many tumor types (1, 2. Previously, we and others have demonstrated that CCL3 plays an essential role in orchestrating T cell—antigen-presenting cell (APC encounters in the draining LN following vaccination, and such interactions enhance the magnitude of the memory T cell pool (3–5. In the current study, we investigate the cellular responses in the tumor-draining lymph nodes (TDLNs of a CCL3-secreting CT26 colon tumor (L3TU as compared to wild-type tumor (WTTU during the priming phase of an antitumor response (≤10 days. In comparison to WTTU, inoculation of L3TU resulted in suppressed tumor growth, a phenomenon that is accompanied by altered in vivo inflammatory responses on several fronts. Autologous tumor-derived CCL3 (aCCL3 secretion by L3TU bolstered the recruitment of T- and B-lymphocytes, tissue-migratory CD103+ dendritic cells (DCs, and CD49b+ natural killer (NK cells, resulting in significant increases in the differentiation and activation of multiple Interferon-gamma (IFNγ-producing leukocytes in the TDLN. During this early phase of immune priming, NK cells constitute the major producers of IFNγ in the TDLN. CCL3 also enhances CD8+ T cell proliferation and differentiation by augmenting DC capacity to drive T cell activation in the TDLN. Our results revealed that CCL3-dependent IFNγ production and CCL3-induced DC maturation drive the priming of effective antitumor immunity in the TDLN.

  20. Combination of PDT and a DNA demethylating agent produces anti-tumor immune response in a mouse tumor model

    Science.gov (United States)

    Mroz, Pawel; Hamblin, Michael R.

    2009-06-01

    Epigenetic mechanisms, which involve DNA methylation and histone modifications, result in the heritable silencing of genes without a change in their coding sequence. However, these changes must be actively maintained after each cell division rendering them a promising target for pharmacologic inhibition. DNA methyltransferase inhibitors like 5-aza-deoxycytidine (5-aza-dC) induce and/or up-regulate the expression of MAGE-type antigens in human and mice cancer cells. Photodynamic therapy (PDT) has been shown to be an effective locally ablative anti-cancer treatment that has the additional advantage of stimulating tumor-directed immune response. We studied the effects of a new therapy that combined the demethylating agent 5-aza-dC with PDT in the breast cancer model 4T1 syngenic to immunocompetent BALB/c mice. PDT was used as a locally ablating tumor treatment that is capable of eliciting strong and tumor directed immune response while 5-aza-dC pretreatment was used promote de novo induction of the expression of P1A.protein. This is the mouse homolog of human MAGE family antigens and is reported to function as a tumor rejection antigen in certain mouse tumors. This strategy led to an increase in PDT-mediated immune response and better treatment outcome. These results strongly suggest that the MAGE family antigens are important target for PDT mediated immune response but that their expression can be silenced by epigenetic mechanisms. Therefore the possibility that PDT can be combined with epigenetic strategies to elicit anti-tumor immunity in MAGE-positive tumor models is highly clinically significant and should be studied in detail.

  1. Decreased Anti-Tumor Cytotoxic Immunity among Microsatellite-Stable Colon Cancers from African Americans.

    Science.gov (United States)

    Basa, Ranor C B; Davies, Vince; Li, Xiaoxiao; Murali, Bhavya; Shah, Jinel; Yang, Bing; Li, Shi; Khan, Mohammad W; Tian, Mengxi; Tejada, Ruth; Hassan, Avan; Washington, Allen; Mukherjee, Bhramar; Carethers, John M; McGuire, Kathleen L

    2016-01-01

    Colorectal cancer is a leading cause of cancer related deaths in the U.S., with African-Americans having higher incidence and mortality rates than Caucasian-Americans. Recent studies have demonstrated that anti-tumor cytotoxic T lymphocytes provide protection to patients with colon cancer while patients deficient in these responses have significantly worse prognosis. To determine if differences in cytotoxic immunity might play a role in racial disparities in colorectal cancer 258 microsatellite-stable colon tumors were examined for infiltrating immune biomarkers via immunohistochemistry. Descriptive summary statistics were calculated using two-sample Wilcoxon rank sum tests, while linear regression models with log-transformed data were used to assess differences in race and Pearson and Spearman correlations were used to correlate different biomarkers. The association between different biomarkers was also assessed using linear regression after adjusting for covariates. No significant differences were observed in CD8+ (p = 0.83), CD57+ (p = 0.55), and IL-17-expressing (p = 0.63) cell numbers within the tumor samples tested. When infiltration of granzyme B+ cells was analyzed, however, a significant difference was observed, with African Americans having lower infiltration of cells expressing this cytotoxic marker than Caucasians (p<0.01). Analysis of infiltrating granzyme B+ cells at the invasive borders of the tumor revealed an even greater difference by race (p<0.001). Taken together, the data presented suggest differences in anti-tumor immune cytotoxicity may be a contributing factor in the racial disparities observed in colorectal cancer.

  2. T-cell mediated anti-tumor immunity after photodynamic therapy: Why does it not always work and how can we improve it?

    Science.gov (United States)

    de Freitas, Lucas Freitas; Hamblin, Michael R

    2015-01-01

    Photodynamic therapy (PDT) uses the combination of non-toxic photosensitizers and harmless light to generate reactive oxygen species that destroy tumors by a combination of direct tumor cell killing, vascular shutdown, and activation of the immune system. It has been shown in some animal models that mice that have been cured of cancer by PDT, may exhibit resistance to rechallenge. The cured mice can also possess tumor specific T-cells that recognize defined tumor antigens, destroy tumor cells in vitro, and can be adoptively transferred to protect naïve mice from cancer. However, these beneficial outcomes are the exception rather than the rule. The reasons for this lack of consistency lie in the ability of many tumors to suppress the host immune system and to actively evade immune attack. The presence of an appropriate tumor rejection antigen in the particular tumor cell line is a requisite for T-cell mediated immunity. Regulatory T-cells (CD25+, Foxp3+) are potent inhibitors of anti-tumor immunity, and their removal by low dose cyclophosphamide can potentiate the PDT-induced immune response. Treatments that stimulate dendritic cells (DC) such as CpG oligonucleotide can overcome tumor-induced DC dysfunction and improve PDT outcome. Epigenetic reversal agents can increase tumor expression of MHC class I and also simultaneously increase expression of tumor antigens. A few clinical reports have shown that anti-tumor immunity can be generated by PDT in patients, and it is hoped that these combination approaches may increase tumor cures in patients. PMID:26062987

  3. Dysregulation of innate immunity in ulcerative colitis patients who fail anti-tumor necrosis factor therapy.

    Science.gov (United States)

    Baird, Angela C; Mallon, Dominic; Radford-Smith, Graham; Boyer, Julien; Piche, Thierry; Prescott, Susan L; Lawrance, Ian C; Tulic, Meri K

    2016-11-07

    To study the innate immune function in ulcerative colitis (UC) patients who fail to respond to anti-tumor necrosis factor (TNF) therapy. Effects of anti-TNF therapy, inflammation and medications on innate immune function were assessed by measuring peripheral blood mononuclear cell (PBMC) cytokine expression from 18 inflammatory bowel disease patients pre- and 3 mo post-anti-TNF therapy. Toll-like receptor (TLR) expression and cytokine production post TLR stimulation was assessed in UC "responders" ( n = 12) and "non-responders" ( n = 12) and compared to healthy controls ( n = 12). Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were measured in blood to assess disease severity/activity and inflammation. Pro-inflammatory (TNF, IL-1β, IL-6), immuno-regulatory (IL-10), Th1 (IL-12, IFNγ) and Th2 (IL-9, IL-13, IL-17A) cytokine expression was measured with enzyme-linked immunosorbent assay while TLR cellular composition and intracellular signalling was assessed with FACS. Prior to anti-TNF therapy, responders and non-responders had similar level of disease severity and activity. PBMC's ability to respond to TLR stimulation was not affected by TNF therapy, patient's severity of the disease and inflammation or their medication use. At baseline, non-responders had elevated innate but not adaptive immune responses compared to responders ( P innate cytokine responses to all TLRs compared to healthy controls ( P innate immune dysfunction was associated with reduced number of circulating plasmacytoid dendritic cells (pDCs) ( P innate immunity in non-responders may explain reduced efficacy to anti-TNF therapy. These serological markers may prove useful in predicting the outcome of costly anti-TNF therapy.

  4. A novel polysaccharide from Ganoderma atrum exerts antitumor activity by activating mitochondria-mediated apoptotic pathway and boosting the immune system.

    Science.gov (United States)

    Zhang, Shenshen; Nie, Shaoping; Huang, Danfei; Feng, Yanling; Xie, Mingyong

    2014-02-19

    Ganoderma is a precious health-care edible medicinal fungus in China. A novel Ganoderma atrum polysaccharide (PSG-1) is the main bioactive component. We investigated the antitumor effect and molecular mechanisms of PSG-1. It exhibited no significant effect on cell proliferation directly. In contrast, administration of PSG-1 markedly suppressed tumor growth in CT26 tumor-bearing mice. It was observed that PSG-1 caused apoptosis in CT26 cells. Apoptosis was associated with loss of mitochondrial membrane potential, enhancement of mitochondrial cytochrome c release and intracellular ROS production, elevation of p53 and Bax expression, downregulation of Bcl-2, and the activation of caspase-9 and -3. Moreover, PSG-1 enhanced immune organ index and promoted lymphocyte proliferation as well as cytokine levels in serum. Taken together, our data indicate that PSG-1 has potential antitumor activity in vivo by inducing apoptosis via mitochondria-mediated apoptotic pathway and enhances host immune system function. Therefore, PSG-1 could be a safe and effective antitumor, bioactive agent or functional food.

  5. Neurofibromin 1 Impairs Natural Killer T-Cell-Dependent Antitumor Immunity against a T-Cell Lymphoma

    Directory of Open Access Journals (Sweden)

    Jianyun Liu

    2018-01-01

    Full Text Available Neurofibromin 1 (NF1 is a tumor suppressor gene encoding a Ras GTPase that negatively regulates Ras signaling pathways. Mutations in NF1 are linked to neurofibromatosis type 1, juvenile myelomonocytic leukemia and Watson syndrome. In terms of antitumor immunity, CD1d-dependent natural killer T (NKT cells play an important role in the innate antitumor immune response. Generally, Type-I NKT cells protect (and Type-II NKT cells impair host antitumor immunity. We have previously shown that CD1d-mediated antigen presentation to NKT cells is regulated by cell signaling pathways. To study whether a haploinsufficiency in NF1 would affect CD1d-dependent activation of NKT cells, we analyzed the NKT-cell population as well as the functional expression of CD1d in Nf1+/− mice. Nf1+/− mice were found to have similar levels of NKT cells as wildtype (WT littermates. Interestingly, however, reduced CD1d expression was observed in Nf1+/− mice compared with their WT littermates. When inoculated with a T-cell lymphoma in vivo, Nf1+/− mice survived longer than their WT littermates. Furthermore, blocking CD1d in vivo significantly enhanced antitumor activity in WT, but not in Nf1+/− mice. In contrast, a deficiency in Type-I NKT cells increased antitumor activity in Nf1+/− mice, but not in WT littermates. Therefore, these data suggest that normal NF1 expression impairs CD1d-mediated NKT-cell activation and antitumor activity against a T-cell lymphoma.

  6. Protein Kinase C-theta (PKC-theta in Natural Killer (NK cell function and anti-tumor immunity

    Directory of Open Access Journals (Sweden)

    Alberto eAnel

    2012-07-01

    Full Text Available The protein kinase C-theta (PKCtheta, which is essential for T cell function and survival, is also required for efficient anti-tumor immune surveillance. Natural killer (NK cells, which express PKCtheta, play a prominent role in this process, mainly by elimination of tumor cells with reduced or absent major histocompatibility complex class-I (MHC-I expression. This justifies the increased interest of the use of activated NK cells in anti-tumor immunotherapy in the clinic. The in vivo development of MHC-I-deficient tumors is much favored in PKCtheta-/- mice compared with wild-type mice. Recent data offer some clues on the mechanism that could explain the important role of PKCtheta in NK cell-mediated anti-tumor immune surveillance: some studies show that PKCtheta is implicated in signal transduction and anti-tumoral activity of NK cells elicited by interleukin (IL-12 or IL-15, while others show that it is implicated in NK cell functional activation mediated by certain killer activating receptors (KAR. Alternatively, the possibility that PKCtheta is involved in NK cell degranulation is discussed, since recent data indicate that it is implicated in microtubule-organizing center (MTOC polarization to the immune synapse in CD4+ T cells. The implication of PKC isoforms in degranulation has been more extensively studied in CTL, and these studies will be also summarized.

  7. Anti-tumor immunity generated by photodynamic therapy in a metastatic murine tumor model

    Science.gov (United States)

    Castano, Ana P.; Hamblin, Michael R.

    2005-04-01

    Photodynamic therapy (PDT) is a modality for the treatment of cancer involving excitation of photosensitizers with harmless visible light producing reactive oxygen species. The major biological effects of PDT are apoptosis of tumor cells, destruction of the blood supply and activation of the immune system. The objective of this study is to compare in an animal model of metastatic cancer, PDT alone and PDT combined with low-dose cyclophosphamide (CY). Since the tumor we used is highly metastatic, it is necessary to generate anti-tumor immunity using PDT to both cure the primary tumor and prevent death from metastasis. This immunity may be potentiated by low dose CY. In our model we used J774 cells (a Balb/c reticulum cell sarcoma line with the characteristics of macrophages) and the following PDT regimen: benzoporphyrin derivative monoacid ring A (BPD, 2mg/kg injected IV followed after 15 min by 150 J/cm2 of 690-nm light). CY (50 mg/kg i.p.) was injected 48 hours before light delivery. BPD-PDT led to complete regression of the primary tumor in more than half the mice but no permanent cures were obtained. BPD-PDT in combination with CY led to 60% permanent cures. CY alone gave no permanent cures but did provide a survival advantage. To probe permanent immunity cured animals were rechallenged with the same tumor cell line and the tumors were rejected in 71% of mice cured with BPD-PDT plus CY. We conclude that BPD-PDT in combination with CY gives best overall results and that this is attributable to immunological response activation in addition to PDT-mediated destruction of the tumor.

  8. Co-delivery of antigen and IL-12 by Venezuelan equine encephalitis virus replicon particles enhances antigen-specific immune responses and anti-tumor effects

    Science.gov (United States)

    Osada, Takuya; Berglund, Peter; Morse, Michael A.; Hubby, Bolyn; Lewis, Whitney; Niedzwiecki, Donna; Hobeika, Amy; Burnett, Bruce; Devi, Gayathri R.; Clay, Timothy M.; Smith, Jonathan; Lyerly, H. Kim

    2013-01-01

    We recently demonstrated that Venezuelan equine encephalitis (VEE) virus-based replicon particles (VRP) encoding tumor antigens could break tolerance in the immunomodulatory environment of advanced cancer. We hypothesized that local injection of VRP expressing Interleukin-12 (IL-12) at the site of injections of VRP-based cancer vaccines would enhance the tumor-antigen-specific T cell and antibody responses and anti-tumor efficacy. Mice were immunized with VRP encoding the human tumor-associated antigen, carcinoembryonic antigen (CEA) (VRP-CEA(6D)) and VRP-IL-12 was also administered at the same site or at a distant location. CEA-specific T cell and antibody responses were measured. To determine antitumor activity, mice were implanted with MC38-CEA-2 cells and immunized with VRP-CEA with and without VRP-IL-12 and tumor growth and mouse survival were measured. VRP-IL-12 greatly enhanced CEA-specific T cell and antibody responses when combined with VRP-CEA(6D) vaccination. VRP IL-12 was superior to IL-12 protein at enhancing immune responses. Vaccination with VRP-CEA(6D) plus VRP-IL-12 was superior to VRP-CEA(6D) or VRP-IL-12 alone in inducing anti-tumor activity and prolonging survival in tumor-bearing mice. Importantly, local injection of VRP-IL-12 at the VRP-CEA(6D) injection site provided more potent activation of CEA-specific immune responses than VRP-IL-12 injected at a distant site from the VRP-CEA injections. Together, this study shows that VRP-IL-12 enhances vaccination with VRP-CEA(6D) and was more effective at activating CEA-specific T cell responses when locally expressed at the vaccine site. Clinical trials evaluating the adjuvant effect of VRP-IL-12 at enhancing the immunogenicity of cancer vaccines are warranted. PMID:22488274

  9. Possible stimulation of anti-tumor immunity using repeated cold stress: a hypothesis

    Directory of Open Access Journals (Sweden)

    Radoja Sasa

    2007-11-01

    Full Text Available Abstract Background The phenomenon of hormesis, whereby small amounts of seemingly harmful or stressful agents can be beneficial for the health and lifespan of laboratory animals has been reported in literature. In particular, there is accumulating evidence that daily brief cold stress can increase both numbers and activity of peripheral cytotoxic T lymphocytes and natural killer cells, the major effectors of adaptive and innate tumor immunity, respectively. This type of regimen (for 8 days has been shown to improve survival of mice infected with intracellular parasite Toxoplasma gondii, which would also be consistent with enhanced cell-mediated immunity. Presentation of the hypothesis This paper hypothesizes that brief cold-water stress repeated daily over many months could enhance anti-tumor immunity and improve survival rate of a non-lymphoid cancer. The possible mechanism of the non-specific stimulation of cellular immunity by repeated cold stress appears to involve transient activation of the sympathetic nervous system, hypothalamic-pituitary-adrenal and hypothalamic-pituitary-thyroid axes, as described in more detail in the text. Daily moderate cold hydrotherapy is known to reduce pain and does not appear to have noticeable adverse effects on normal test subjects, although some studies have shown that it can cause transient arrhythmias in patients with heart problems and can also inhibit humoral immunity. Sudden immersion in ice-cold water can cause transient pulmonary edema and increase permeability of the blood-brain barrier, thereby increasing mortality of neurovirulent infections. Testing the hypothesis The proposed procedure is an adapted cold swim (5–7 minutes at 20 degrees Celsius, includes gradual adaptation to be tested on a mouse tumor model. Mortality, tumor size, and measurements of cellular immunity (numbers and activity of peripheral CD8+ T lymphocytes and natural killer cells of the cold-exposed group would be compared to

  10. Immunogenic Cell Death Induced by Ginsenoside Rg3: Significance in Dendritic Cell-based Anti-tumor Immunotherapy.

    Science.gov (United States)

    Son, Keum-Joo; Choi, Ki Ryung; Lee, Seog Jae; Lee, Hyunah

    2016-02-01

    Cancer is one of the leading causes of morbidity and mortality worldwide; therefore there is a need to discover new therapeutic modules with improved efficacy and safety. Immune-(cell) therapy is a promising therapeutic strategy for the treatment of intractable cancers. The effectiveness of certain chemotherapeutics in inducing immunogenic tumor cell death thus promoting cancer eradication has been reported. Ginsenoside Rg3 is a ginseng saponin that has antitumor and immunomodulatory activity. In this study, we treated tumor cells with Rg3 to verify the significance of inducing immunogenic tumor cell death in antitumor therapy, especially in DC-based immunotherapy. Rg3 killed the both immunogenic (B16F10 melanoma cells) and non-immunogenic (LLC: Lewis Lung Carcinoma cells) tumor cells by inducing apoptosis. Surface expression of immunogenic death markers including calreticulin and heat shock proteins and the transcription of relevant genes were increased in the Rg3-dying tumor. Increased calreticulin expression was directly related to the uptake of dying tumor cells by dendritic cells (DCs): the proportion of CRT(+) CD11c(+) cells was increased in the Rg3-treated group. Interestingly, tumor cells dying by immunogenic cell death secreted IFN-γ, an effector molecule for antitumor activity in T cells. Along with the Rg3-induced suppression of pro-angiogenic (TNF-α) and immunosuppressive cytokine (TGF-β) secretion, IFN-γ production from the Rg3-treated tumor cells may also indicate Rg3 as an effective anticancer immunotherapeutic strategy. The data clearly suggests that Rg3-induced immunogenic tumor cell death due its cytotoxic effect and its ability to induce DC function. This indicates that Rg3 may be an effective immunotherapeutic strategy.

  11. Photodynamic therapy stimulates anti-tumor immunity in a murine model

    Science.gov (United States)

    Mroz, Pawel; Castano, Ana P.; Wu, Mei X.; Kung, Andrew L.; Hamblin, Michael R.

    2007-02-01

    Cancer is a leading cause of death among modern peoples largely due to metastatic disease. The ideal cancer treatment should target both the primary tumor and the metastases with the minimal toxicity. This is best accomplished by educating the body's immune system to recognize the tumor as foreign so that after the primary tumor is destroyed, distant metastases will also be eradicated. Photodynamic therapy (PDT) involves the IV administration of photosensitizers followed by illumination of the primary tumor with red light producing reactive oxygen species that cause vascular shutdown and tumor cell apoptosis. Anti-tumor immunity is stimulated after PDT due to the acute inflammatory response, priming of the immune system to recognize tumor-associated antigens (TAA), and induction of heat-shock proteins. The induction of specific CD8+ T lymphocyte cells that recognize major histocompatibility complex class I (MHC-I) restricted epitopes of TAAs is a highly desirable goal in cancer therapy. We here report on PDT of mice bearing tumors that either do or do not express an established TAA. We utilized a BALB/c colon adenocarcinoma cell line termed CT26.CL25 retrovirally transduced to stably express β-galactosidase ( β-gal, a bacterial protein), and its non-β-gal expressing wild-type counterpart termed CT26 WT, as well as the control cell line consisting of CT26 transduced with the empty retroviral vector termed CT26-neo. All cells expressed class I MHC restriction element H-2Ld syngenic to BALB/c mice. Vascular PDT with a regimen of 1mg/kg BPD injected IV, and 120 J/cm2 of 690-nm laser light after 15 minutes successfully cured 100% of CT26.CL25 tumors but 0% of CT26-neo tumors and 0% of CT26 WT tumors. After 90 days tumor free interval the CT26.CL25 cured mice were rechallenged with CT26.CL25 tumor cells and 96% rejected the rechallenge while the CT26.CL25 cured mice did not reject a CT26 WT tumor cell challenge. Experiments with mice bearing two CT26.CL25 tumors (one

  12. Amplexicaule A exerts anti-tumor effects by inducing apoptosis in human breast cancer

    Science.gov (United States)

    Shu, Guangwen; Wan, Dingrong; He, Feng; Loaec, Morgann; Ding, Yali; Li, Jun; Dovat, Sinisa; Yang, Gaungzhong; Song, Chunhua

    2016-01-01

    Chemotherapy is the main treatment for patients with breast cancer metastases, but natural alternatives have been receiving attention for their potential as novel anti-tumor reagents. Amplexicaule A (APA) is a flavonoid glucoside isolated from rhizomes of Polygonum amplexicaule D. Don var. sinense Forb (PADF). We found that APA has anti-tumor effects in a breast cancer xenograft mouse model and induces apoptosis in breast cancer cell lines. APA increased levels of cleaved caspase-3,-8,-9 and PARP, which resulted from suppression of MCL-1 and BCL-2 expression in the cells. APA also inactivated the Akt/mTOR pathway in breast cancer cells. Thus, APA exerts a strong anti-tumor effect on breast cancer cells, most likely through induction of apoptosis. Our study is the first to identify this novel anti-tumor compound and provides a new strategy for isolation and separation of single compounds from herbs. PMID:26943775

  13. Photodynamic therapy stimulates anti-tumor immune response in mouse models: the role of regulatory Tcells, anti-tumor antibodies, and immune attacks on brain metastases

    Science.gov (United States)

    Vatansever, Fatma; Kawakubo, Masayoshi; Chung, Hoon; Hamblin, Michael R.

    2013-02-01

    We have previously shown that photodynamic therapy mediated by a vascular regimen of benzoporphyrin derivative and 690nm light is capable of inducing a robust immune response in the mouse CT26.CL25 tumor model that contains a tumor-rejection antigen, beta-galactosidase (β-gal). For the first time we show that PDT can stimulate the production of serum IgG antibodies against the β-gal antigen. It is known that a common cause of death from cancer, particularly lung cancer, is brain metastases; especially the inoperable ones that do not respond to traditional cytotoxic therapies either. We asked whether PDT of a primary tumor could stimulate immune response that could attack the distant brain metastases. We have developed a mouse model of generating brain metastases by injecting CT26.CL25 tumor cells into the brain as well as injecting the same cancer cells under the skin at the same time. When the subcutaneous tumor was treated with PDT, we observed a survival advantage compared to mice that had untreated brain metastases alone.

  14. Dual antibody therapy to harness the innate anti-tumor immune response to enhance antibody targeting of tumors.

    Science.gov (United States)

    Chester, Cariad; Marabelle, Aurelien; Houot, Roch; Kohrt, Holbrook E

    2015-04-01

    Cancer immunotherapy is a rapidly evolving field that offers a novel paradigm for cancer treatment: therapies focus on enhancing the immune system's innate and adaptive anti-tumor response. Early immunotherapeutics have achieved impressive clinical outcomes and monoclonal antibodies are now integral to therapeutic strategies in a variety of cancers. However, only recently have antibodies targeting innate immune cells entered clinical development. Innate immune effector cells play important roles in generating and maintaining antitumor immunity. Antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) are important innate immune mechanisms for tumor eradication. These cytolytic processes are initiated by the detection of a tumor-targeting antibody and can be augmented by activating co-stimulatory pathways or blocking inhibitory signals on innate immune cells. The combination of FDA-approved monoclonal antibodies with innate effector-targeting antibodies has demonstrated potent preclinical therapeutic synergy and early-phase combinatorial clinical trials are ongoing. Copyright © 2015 Elsevier Ltd. All rights reserved.

  15. Ectopic expression of X-linked lymphocyte-regulated protein pM1 renders tumor cells resistant to antitumor immunity.

    Science.gov (United States)

    Kang, Tae Heung; Noh, Kyung Hee; Kim, Jin Hee; Bae, Hyun Cheol; Lin, Ken Y; Monie, Archana; Pai, Sara I; Hung, Chien-Fu; Wu, T-C; Kim, Tae Woo

    2010-04-15

    Tumor immune escape is a major obstacle in cancer immunotherapy, but the mechanisms involved remain poorly understood. We have previously developed an immune evasion tumor model using an in vivo immune selection strategy and revealed Akt-mediated immune resistance to antitumor immunity induced by various cancer immunotherapeutic agents. In the current study, we used microarray gene analysis to identify an Akt-activating candidate molecule overexpressed in immune-resistant tumors compared with parental tumors. X-linked lymphocyte-regulated protein pM1 (XLR) gene was the most upregulated in immune-resistant tumors compared with parental tumor cells. Furthermore, the retroviral transduction of XLR in parental tumor cells led to activation of Akt, resulting in upregulation of antiapoptotic proteins and the induction of immune resistance phenotype in parental tumor cells. In addition, we found that transduction of parental tumor cells with other homologous genes from the mouse XLR family, such as synaptonemal complex protein 3 (SCP3) and XLR-related, meiosis-regulated protein (XMR) and its human counterpart of SCP3 (hSCP3), also led to activation of Akt, resulting in the upregulation of antiapoptotic proteins and induction of immune resistance phenotype. Importantly, characterization of a panel of human cervical cancers revealed relatively higher expression levels of hSCP3 in human cervical cancer tissue compared with normal cervical tissue. Thus, our data indicate that ectopic expression of XLR and its homologues in tumor cells represents a potentially important mechanism for tumor immune evasion and serves as a promising molecular target for cancer immunotherapy. (c) 2010 AACR.

  16. Defining the role of the tumor vasculature in antitumor immunity and immunotherapy.

    Science.gov (United States)

    Schaaf, Marco B; Garg, Abhishek D; Agostinis, Patrizia

    2018-01-25

    It is now well established that cancer cells co-exist within a complex environment with stromal cells and depend for their growth and dissemination on tight and plastic interactions with components of the tumor microenvironment (TME). Cancer cells incite the formation of new blood and lymphatic vessels from preexisting vessels to cope with their high nutrient/oxygen demand and favor tumor outgrowth. Research over the past decades has highlighted the crucial role played by tumor-associated blood and lymphatic vasculature in supporting immunoevasion and in subverting T-cell-mediated immunosurveillance, which are the main hallmarks of cancers. The structurally and functionally aberrant tumor vasculature contributes to the protumorigenic and immunosuppressive TME by maintaining a cancer cell's permissive environment characterized by hypoxia, acidosis, and high interstitial pressure, while simultaneously generating a physical barrier to T cells' infiltration. Recent research moreover has shown that blood endothelial cells forming the tumor vessels can actively suppress the recruitment, adhesion, and activity of T cells. Likewise, during tumorigenesis the lymphatic vasculature undergoes dramatic remodeling that facilitates metastatic spreading of cancer cells and immunosuppression. Beyond carcinogenesis, the erratic tumor vasculature has been recently implicated in mechanisms of therapy resistance, including those limiting the efficacy of clinically approved immunotherapies, such as immune checkpoint blockers and adoptive T-cell transfer. In this review, we discuss emerging evidence highlighting the major role played by tumor-associated blood and lymphatic vasculature in thwarting immunosurveillance mechanisms and antitumor immunity. Moreover, we also discuss novel therapeutic approaches targeting the tumor vasculature and their potential to help overcoming immunotherapy resistance.

  17. Depletion of regulatory T cells by anti-ICOS antibody enhances anti-tumor immunity of tumor cell vaccine in prostate cancer.

    Science.gov (United States)

    Mo, Lijun; Chen, Qianmei; Zhang, Xinji; Shi, Xiaojun; Wei, Lili; Zheng, Dianpeng; Li, Hongwei; Gao, Jimin; Li, Jinlong; Hu, Zhiming

    2017-10-13

    ICOS + Treg cells exert important immunosuppressive effects in tumor immunity. We adopt a combination approach of ICOS + Treg cells depletion with tumor cell vaccine to evaluate anti-tumor immunity in mouse prostate cancer model. Streptavidin (SA)-mGM-CSF surface-modified RM-1 cells were prepared as the vaccine and the mouse subcutaneous prostate tumor model was used to evaluate the immunity. Tumor growth, flow cytometry, immunohistochemistry, immunofluorescence and enzyme linked immunosorbent assay (ELISA) were performed to evaluate the therapeutic effects. Our results demonstrated that SA-mGM-CSF vaccine was prepared successfully and tumor growth was inhibited. The tumor size in the combination group was much smaller than that in the vaccine with IgG mAb group. The portions of dendritic cells, CD8 + and CD4 + T cells in the mice blood and tumor tissues were increased after treatment with vaccine. There were more immune-suppressing Tregs infiltrated into tumor after treatment with tumor cell vaccine, and ICOS blocking could deplete the infiltrated Tregs, and T lymphocytes increased more dramatically in the combination therapy group. The concentrations of interferon-γ were increased in all vaccine group, the concentrations of Interleukin-10 and Interleukin-4 were much lower in the combination group. Our study demonstrated that ICOS blocking could deplete the tumor-infiltrated ICOS + Treg cells. Combining GM-CSF surface-modified RM-1 cell vaccine with Anti-ICOS antibody could induce better antitumor immunity than a vaccine alone. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Specific anti-tumor immune response with photodynamic therapy mediated by benzoporphyrin derivative and chlorin(e6)

    Science.gov (United States)

    Castano, Ana P.; Gad, Faten; Zahra, Touqir; Hamblin, Michael R.

    2003-07-01

    The purpose of this study was to investigate the induction of anti-tumor immunity by photodynamic therapy (PDT). We used EMT-6 mammary sarcoma, a moderately immunogenic tumor, with 10(6) cells injected s.c. in thighs of immunocompetent Balb/c mice. Mice were treated 10 days later when tumors were 6-mm diameter. Two PDT regimens were equally effective in curing tumors: 1-mg/kg of liposomal benzoporphyrin derivative (BPD) followed after 15 min by 150 J/cm2 690 nm light or 10-mg/kg chlorin(e6) (ce6) followed after 6 hours by 150 J/cm2 665 nm light. BPD-PDT produced a black eschar 24-48 hours after treatment with no visible tumor, followed by healing of the lesion. By contrast ce6-PDT showed no black eschar, but a slow disappearance of tumor over 5-7 days. When cured mice were rechallenged with 10(6) EMT-6 cells in the opposite thigh, all ce6-PDT cured mice rejected the challenge, but BPD-PDT cured mice grew tumors in a proportion of cases. When mice were cured by amputation of the tumor bearing leg, all mice subsequently grew tumors upon rechallenge. Mice were given two EMT6 tumors (1 in each leg) and the mouse was injected with ce6 or BPD but only one tumor was treated with light. Both tumors (PDT-treated and contralateral) regressed at an equal rate until they became undetectable, but in some mice the untreated tumor recurred. Those mice cured of both tumors rejected a subsequent EMT6 rechallenge. Amputation of the tumor bearing leg did not lead to regression of the contralateral tumor. Mice that rejected an EMT6 rechallenge failed to reject a subsequent cross-challenge with J774 reticulum cell sarcoma (an alternative Balb/c murine tumor). These data show that PDT generates a tumor-specific memory immune response, and in addition an active tumoricidal immune response capable of destroying distant established tumors. We hypothesize that ce6-PDT is more effective than BPD-PDT due to more necrotic rather than apoptotic cell death and/or generation of heat

  19. Adrenergic Signaling: A Targetable Checkpoint Limiting Development of the Antitumor Immune Response.

    Science.gov (United States)

    Qiao, Guanxi; Chen, Minhui; Bucsek, Mark J; Repasky, Elizabeth A; Hylander, Bonnie L

    2018-01-01

    An immune response must be tightly controlled so that it will be commensurate with the level of response needed to protect the organism without damaging normal tissue. The roles of cytokines and chemokines in orchestrating these processes are well known, but although stress has long been thought to also affect immune responses, the underlying mechanisms were not as well understood. Recently, the role of nerves and, specifically, the sympathetic nervous system, in regulating immune responses is being revealed. Generally, an acute stress response is beneficial but chronic stress is detrimental because it suppresses the activities of effector immune cells while increasing the activities of immunosuppressive cells. In this review, we first discuss the underlying biology of adrenergic signaling in cells of both the innate and adaptive immune system. We then focus on the effects of chronic adrenergic stress in promoting tumor growth, giving examples of effects on tumor cells and immune cells, explaining the methods commonly used to induce stress in preclinical mouse models. We highlight how this relates to our observations that mandated housing conditions impose baseline chronic stress on mouse models, which is sufficient to cause chronic immunosuppression. This problem is not commonly recognized, but it has been shown to impact conclusions of several studies of mouse physiology and mouse models of disease. Moreover, the fact that preclinical mouse models are chronically immunosuppressed has critical ramifications for analysis of any experiments with an immune component. Our group has found that reducing adrenergic stress by housing mice at thermoneutrality or treating mice housed at cooler temperatures with β-blockers reverses immunosuppression and significantly improves responses to checkpoint inhibitor immunotherapy. These observations are clinically relevant because there are numerous retrospective epidemiological studies concluding that cancer patients who were

  20. Enhanced antitumor immunity contributes to the radio-sensitization of ehrlich ascites tumor by the glycolytic inhibitor 2-deoxy-D-glucose in mice.

    Directory of Open Access Journals (Sweden)

    Abdullah Farooque

    Full Text Available Two-deoxy-D-glucose (2-DG, an inhibitor of glycolysis differentially enhances the radiation and chemotherapeutic drug induced cell death in cancer cells in vitro, while the local tumor control (tumor regression following systemic administration of 2-DG and focal irradiation of the tumor results in both complete (cure and partial response in a fraction of the tumor bearing mice. In the present studies, we investigated the effects of systemically administered 2-DG and focal irradiation of the tumor on the immune system in Ehrlich ascites tumor (EAT bearing Strain "A" mice. Markers of different immune cells were analyzed by immune-flow cytometry and secretary cytokines by ELISA, besides monitoring tumor growth. Increase in the expression of innate (NK and monocytes and adaptive CD4+cells, and a decrease in B cells (CD19 have been observed after the combined treatment, suggestive of activation of anti-tumor immune response. Interestingly, immature dendritic cells were found to be down regulated, while their functional markers CD86 and MHC II were up regulated in the remaining dendritic cells following the combination treatment. Similarly, decrease in the CD4(+ naïve cells with concomitant increase in activated CD4+ cells corroborated the immune activation. Further, a shift from Th2 and Th17 to Th1 besides a decrease in inflammatory cytokines was also observed in the animals showing complete response (cure; tumor free survival. This shift was also complimented by respective antibody class switching followed by the combined treatment. The immune activation or alteration in the homeostasis favoring antitumor immune response may be due to depletion in T regulatory cells (CD4(+CD25(+FoxP3(+. Altogether, these results suggest that early differential immune activation is responsible for the heterogenous response to the combined treatment. Taken together, these studies for the first time provided insight into the additional mechanisms underlying radio

  1. Anti-tumor response induced by immunologically modified carbon nanotubes and laser irradiation using rat mammary tumor model

    Directory of Open Access Journals (Sweden)

    Joseph T. Acquaviva

    2015-07-01

    Full Text Available The ideal treatment modality for metastatic cancer would be a local treatment that can destroy primary tumors while inducing an effective systemic anti-tumor response. To this end, we developed laser immunotherapy, combining photothermal laser application with an immunoadjuvant for the treatment of metastatic cancer. Additionally, to enhance the selective photothermal effect, we integrated light-absorbing nanomaterials into this innovative treatment. Specifically, we developed an immunologically modified carbon nanotube combining single-walled carbon nanotubes (SWNTs with the immunoadjuvant glycated chitosan (GC. To determine the effectiveness of laser irradiation, a series of experiments were performed using two different irradiation durations — 5 and 10 min. Rats were inoculated with DMBA-4 cancer cells, a metastatic cancer cell line. The treatment group of rats receiving laser irradiation for 10 min had a 50% long-term survival rate without residual primary or metastatic tumors. The treatment group of rats receiving laser irradiation for 5 min had no long-term survivors; all rats died with multiple metastases at several distant sites. Therefore, Laser+SWNT–GC treatment with 10 min of laser irradiation proved to be effective at reducing tumor size and inducing long-term anti-tumor immunity.

  2. MUC1-specific immune therapy generates a strong anti-tumor response in a MUC1-tolerant colon cancer model.

    Science.gov (United States)

    Mukherjee, P; Pathangey, L B; Bradley, J B; Tinder, T L; Basu, G D; Akporiaye, E T; Gendler, S J

    2007-02-19

    A MUC1-based vaccine was used in a preclinical model of colon cancer. The trial was conducted in a MUC1-tolerant immune competent host injected with MC38 colon cancer cells expressing MUC1. The vaccine included: MHC class I-restricted MUC1 peptides, MHC class II-restricted pan-helper-peptide, unmethylated CpG oligodeoxynucleotide, and granulocyte macrophage-colony stimulating factor. Immunization was successful in breaking MUC1 self-tolerance, and in eliciting a robust anti-tumor response. The vaccine stimulated IFN-gamma-producing CD4(+) helper and CD8(+) cytotoxic T cells against MUC1 and other undefined MC38 tumor antigens. In the prophylactic setting, immunization caused complete rejection of tumor cells, while in the therapeutic regimen, tumor burden was significantly reduced.

  3. OK-432 synergizes with IFN-γ to confer dendritic cells with enhanced antitumor immunity.

    Science.gov (United States)

    Pan, Ke; Lv, Lin; Zheng, Hai-xia; Zhao, Jing-jing; Pan, Qiu-zhong; Li, Jian-jun; Weng, De-sheng; Wang, Dan-dan; Jiang, Shan-shan; Chang, Alfred E; Li, Qiao; Xia, Jian-chuan

    2014-03-01

    Generation of functional dendritic cells (DCs) with boosted immunity after the withdrawal of initial activation/maturation conditions remains a significant challenge. In this study, we investigated the impact of a newly developed maturation cocktail consisting of OK-432 and interferon-gamma (IFN-γ) on the function of human monocyte-derived DCs (MoDCs). We found that OK-432 plus IFN-γ stimulation could induce significantly stronger expression of surface molecules, production of cytokines, as well as migration of DCs compared with OK-432 stimulation alone. Most importantly, DCs matured with OK-432 plus IFN-γ-induced maintained secretion of interleukin-12 (IL-12)p70 in secondary culture after stimulus withdrawal. Functionally, OK-432 plus IFN-γ-conditioned DCs induce remarkable Th1 and Tc1 responses more effectively than OK-432 alone, even more than the use of α-type-1 cytokine cocktail. As a result, DCs matured with OK-432 plus IFN-γ can prime stronger cytotoxic lymphocyte (CTL) and natural killer (NK) cell response against tumor cells in vitro. Peripheral blood mononuclear cells activated by DCs matured with OK-432 plus IFN-γ also showed greater tumor growth inhibition in vivo in null mice. Molecular mechanistic analysis showed that DC maturation using IFN-γ in concert with OK-432 involves the activation of p38 and nuclear factor-kappa B (NF-κB) pathways. This study provided a novel strategy to generate more potent immune segments in DC vaccine.

  4. A Toll-like receptor 2 agonist-fused antigen enhanced antitumor immunity by increasing antigen presentation and the CD8 memory T cells population.

    Science.gov (United States)

    Wu, Chiao-Chieh; Liu, Shih-Jen; Chen, Hsin-Wei; Shen, Kuan-Yin; Leng, Chih-Hsiang

    2016-05-24

    The induction of long-lived effector CD8+ T cells is key to the development of efficient cancer vaccines. In this study, we demonstrated that a Toll-like receptor 2 (TLR2) agonist-fused antigen increased antigen presentation via TLR2 signaling and induced effector memory-like CD8+ T cells against cancer after immunization. The N-terminus of ovalbumin (OVA) was biologically fused with a bacterial lipid moiety TLR2 agonist to produce a recombinant lipidated ovalbumin (rlipo-OVA). We demonstrated that rlipo-OVA activated bone marrow-derived dendritic cells (BM-DCs) maturation and increased antigen presentation by major histocompatibility complex (MHC) class I via TLR2. After immunization, rlipo-OVA skewed the immune response towards T helper (Th) 1 and induced OVA-specific cytotoxic T lymphocyte (CTL) responses. Moreover, immunization with rlipo-OVA induced higher numbers of effector memory (CD44+CD62L-) CD8+ T cells compared with recombinant ovalbumin (rOVA) alone or rOVA mixed with the TLR2 agonist Pam3CSK4. Accordingly, the CD27+CD43+ effector memory CD8+ T cells expressed high levels of the long-lived CD127 marker. The administration of rlipo-OVA could inhibit tumor growth, but the anti-tumor effects were lost after the depletion of CD8 or CD127 cells in vivo. These findings suggested that the TLR2 agonist-fused antigen induced long-lived memory CD8+ T cells for efficient cancer therapy.

  5. Ezh2 phosphorylation state determines its capacity to maintain CD8+T memory precursors for antitumor immunity.

    Science.gov (United States)

    He, Shan; Liu, Yongnian; Meng, Lijun; Sun, Hongxing; Wang, Ying; Ji, Yun; Purushe, Janaki; Chen, Pan; Li, Changhong; Madzo, Jozef; Issa, Jean-Pierre; Soboloff, Jonathan; Reshef, Ran; Moore, Bethany; Gattinoni, Luca; Zhang, Yi

    2017-12-14

    Memory T cells sustain effector T-cell production while self-renewing in reaction to persistent antigen; yet, excessive expansion reduces memory potential and impairs antitumor immunity. Epigenetic mechanisms are thought to be important for balancing effector and memory differentiation; however, the epigenetic regulator(s) underpinning this process remains unknown. Herein, we show that the histone methyltransferase Ezh2 controls CD8 + T memory precursor formation and antitumor activity. Ezh2 activates Id3 while silencing Id2, Prdm1 and Eomes, promoting the expansion of memory precursor cells and their differentiation into functional memory cells. Akt activation phosphorylates Ezh2 and decreases its control of these transcriptional programs, causing enhanced effector differentiation at the expense of T memory precursors. Engineering T cells with an Akt-insensitive Ezh2 mutant markedly improves their memory potential and capability of controlling tumor growth compared to transiently inhibiting Akt. These findings establish Akt-mediated phosphorylation of Ezh2 as a critical target to potentiate antitumor immunotherapeutic strategies.

  6. A HLA-A2-restricted CTL epitope induces anti-tumor effects against human lung cancer in mouse xenograft model.

    Science.gov (United States)

    Sher, Yuh-Pyng; Lin, Su-I; Chen, I-Hua; Liu, Hsin-Yu; Lin, Chen-Yuan; Chiang, I-Ping; Roffler, Steve; Chen, Hsin-Wei; Liu, Shih-Jen

    2016-01-05

    Cancer immunotherapy is attractive for antigen-specific T cell-mediated anti-tumor therapy, especially in induction of cytotoxic T lymphocytes. In this report, we evaluated human CTL epitope-induced anti-tumor effects in human lung cancer xenograft models. The tumor associated antigen L6 (TAL6) is highly expressed in human lung cancer cell lines and tumor specimens as compared to normal lung tissues. TAL6 derived peptides strongly inhibited tumor growth, cancer metastasis and prolonged survival time in HLA-A2 transgenic mice immunized with a formulation of T-helper (Th) peptide, synthetic CpG ODN, and adjuvant Montanide ISA-51 (ISA-51). Adoptive transfer of peptide-induced CTL cells from HLA-A2 transgenic mice into human tumor xenograft SCID mice significantly inhibited tumor growth. Furthermore, combination of CTL-peptide immunotherapy and gemcitabine additively improved the therapeutic effects. This pre-clinical evaluation model provides a useful platform to develop efficient immunotherapeutic drugs to treat lung cancer and demonstrates a promising strategy with benefit of antitumor immune responses worthy of further development in clinical trials.

  7. IgG4 subclass antibodies impair antitumor immunity in melanoma.

    Science.gov (United States)

    Karagiannis, Panagiotis; Gilbert, Amy E; Josephs, Debra H; Ali, Niwa; Dodev, Tihomir; Saul, Louise; Correa, Isabel; Roberts, Luke; Beddowes, Emma; Koers, Alexander; Hobbs, Carl; Ferreira, Silvia; Geh, Jenny L C; Healy, Ciaran; Harries, Mark; Acland, Katharine M; Blower, Philip J; Mitchell, Tracey; Fear, David J; Spicer, James F; Lacy, Katie E; Nestle, Frank O; Karagiannis, Sophia N

    2013-04-01

    Host-induced antibodies and their contributions to cancer inflammation are largely unexplored. IgG4 subclass antibodies are present in IL-10-driven Th2 immune responses in some inflammatory conditions. Since Th2-biased inflammation is a hallmark of tumor microenvironments, we investigated the presence and functional implications of IgG4 in malignant melanoma. Consistent with Th2 inflammation, CD22+ B cells and IgG4(+)-infiltrating cells accumulated in tumors, and IL-10, IL-4, and tumor-reactive IgG4 were expressed in situ. When compared with B cells from patient lymph nodes and blood, tumor-associated B cells were polarized to produce IgG4. Secreted B cells increased VEGF and IgG4, and tumor cells enhanced IL-10 secretion in cocultures. Unlike IgG1, an engineered tumor antigen-specific IgG4 was ineffective in triggering effector cell-mediated tumor killing in vitro. Antigen-specific and nonspecific IgG4 inhibited IgG1-mediated tumoricidal functions. IgG4 blockade was mediated through reduction of FcγRI activation. Additionally, IgG4 significantly impaired the potency of tumoricidal IgG1 in a human melanoma xenograft mouse model. Furthermore, serum IgG4 was inversely correlated with patient survival. These findings suggest that IgG4 promoted by tumor-induced Th2-biased inflammation may restrict effector cell functions against tumors, providing a previously unexplored aspect of tumor-induced immune escape and a basis for biomarker development and patient-specific therapeutic approaches.

  8. [The role of extracellular chaperone Hsp70 in creating antitumor immunity in rat rhabdomyosarcoma RA-2 model].

    Science.gov (United States)

    Guzhova, I V; Komarova, E Iu; Pimenova, A A; Bakhtin, Iu B; Kaminskaia, E V; Margulis, B A

    2008-01-01

    Immunization of experimental animals with extract or membranes of rat rhabdomyosarcoma RA-2 in combination with pure Hsp70 did not offer any significant effect of protection from subsequent RA-2 cells-stimulated tumor growth. By contrast, immunization with preparations of pure Hsp70 led to a significant decrease in number and size of tumors as well as elevation of concentrations of antibodies against RA-2 cells. Also, enhanced blood levels of Hsp70 involved delayed tumor growth. In vitro tests Hsp70 incubation with RA-2 cells was followed by a 30-35% rise in cytotoxic lymphocytes levels. An ability of pure Hsp70 preparations to stimulate humoral and antitumor response was demonstrated. Hence, they may be used in developing vaccine formulas.

  9. Effect of linalool as a component of Humulus lupulus on doxorubicin-induced antitumor activity.

    Science.gov (United States)

    Miyashita, Michiko; Sadzuka, Yasuyuki

    2013-03-01

    As malignant neoplasm is a major public health problem, there is a need for the development of a novel modulator that enhances antitumor activity and reduces adverse reactions to antitumor agents. In this study, the effects of some volatile oil components in Humulus lupulus on doxorubicin (DOX) permeability in tumor cells and DOX-induced antitumor activity were examined. In vitro, DOX levels in tumor cells by combined linalool as its component significantly increased in the DOX influx system, and the increased effect by linalool on DOX cytotoxicity was shown. In vivo, the combination of DOX with linalool significantly decreased tumor weight compared with that of DOX alone treated group. The promotion of DOX influx level by combined linalool did not depend on energy, whereas it was suppressed by the absence of Na(+). This promoting effect was suppressed by the presence of S-(4-nitrobenzyl)-6-thioinosine and inhibited dependently on phlorizin concentration. It is considered that linalool promoted DOX influx in tumor cells because of its action on DOX transport through concentrative Na(+)-dependent nucleoside transporter 3, which increased DOX concentration in tumor cells and thus enhanced the antitumor activity of DOX. Therefore, linalool as a food component is anticipated to be an effective DOX modulator. Copyright © 2012 Elsevier Ltd. All rights reserved.

  10. Tumor mouse model confirms MAGE-A3 cancer immunotherapeutic as an efficient inducer of long-lasting anti-tumoral responses.

    Directory of Open Access Journals (Sweden)

    Catherine Gérard

    Full Text Available MAGE-A3 is a potential target for immunotherapy due to its tumor-specific nature and expression in several tumor types. Clinical data on MAGE-A3 immunotherapy have raised many questions that can only be addressed by using animal models. In the present study, different aspects of the murine anti-tumor immune responses induced by a recombinant MAGE-A3 protein (recMAGE-A3 in combination with different immunostimulants (AS01, AS02, CpG7909 or AS15 were investigated.Based on cytokine profile analyses and protection against challenge with MAGE-A3-expressing tumor, the combination recMAGE-A3+AS15 was selected for further experimental work, in particular to study the mechanisms of anti-tumor responses. By using MHC class I-, MHC class II-, perforin-, B-cell- and IFN-γ- knock-out mice and CD4+ T cell-, CD8+ T cell- and NK cell- depleted mice, we demonstrated that CD4+ T cells and NK cells are the main anti-tumor effectors, and that IFN-γ is a major effector molecule. This mouse tumor model also established the need to repeat recMAGE-A3+AS15 injections to sustain efficient anti-tumor responses. Furthermore, our results indicated that the efficacy of tumor rejection by the elicited anti-MAGE-A3 responses depends on the proportion of tumor cells expressing MAGE-A3.The recMAGE-A3+AS15 cancer immunotherapy efficiently induced an antigen-specific, functional and long-lasting immune response able to recognize and eliminate MAGE-A3-expressing tumor cells up to several months after the last immunization in mice. The data highlighted the importance of the immunostimulant to induce a Th1-type immune response, as well as the key role played by IFN-γ, CD4+ T cells and NK cells in the anti-tumoral effect.

  11. Evidence of Anti-tumoral Efficacy in an Immune Competent Setting with an iRGD-Modified Hyaluronidase-Armed Oncolytic Adenovirus

    Directory of Open Access Journals (Sweden)

    Ahmed Abdullah Al-Zaher

    2018-03-01

    Full Text Available To enhance adenovirus-mediated oncolysis, different approaches that tackle the selectivity, tumor penetration, and spreading potential of oncolytic adenoviruses have been reported. We have previously demonstrated that insertion of the internalizing Arginine-Glycine-Aspartic (iRGD tumor-penetrating peptide at the C terminus of the fiber or transgenic expression of a secreted hyaluronidase can improve virus tumor targeting and spreading. Here we report a new oncolytic adenovirus ICOVIR17K-iRGD in which both modifications have been incorporated. In xenografted A549 tumors in nude mice, ICOVIR17K-iRGD shows higher efficacy than the non-iRGD counterpart. To gain insights into the role of the immune system in oncolysis, we have studied ICOVIR17K-iRGD in the tumor isograft mouse model CMT64.6, partially permissive to human adenovirus 5 replication, in immunodeficient or immunocompetent mice. Whereas no efficacy was observed in the immunodeficient setting due to insufficient viral replication, partial efficacy and a polymorphonuclear and CD8+ T cell infiltrate were observed in the immunocompetent mice. The results indicate that the elicitation of a virus-induced anti-tumoral immune response is responsible for the observed partial anti-tumoral effect. Keywords: oncolytic adenovirus, iRGD tumor-penetrating peptide, immune response

  12. The kinase TBK1 functions in dendritic cells to regulate T cell homeostasis, autoimmunity, and antitumor immunity.

    Science.gov (United States)

    Xiao, Yichuan; Zou, Qiang; Xie, Xiaoping; Liu, Ting; Li, Haiyan S; Jie, Zuliang; Jin, Jin; Hu, Hongbo; Manyam, Ganiraju; Zhang, Li; Cheng, Xuhong; Wang, Hui; Marie, Isabelle; Levy, David E; Watowich, Stephanie S; Sun, Shao-Cong

    2017-05-01

    Dendritic cells (DCs) are crucial for mediating immune responses but, when deregulated, also contribute to immunological disorders, such as autoimmunity. The molecular mechanism underlying the function of DCs is incompletely understood. In this study, we have identified TANK-binding kinase 1 (TBK1), a master innate immune kinase, as an important regulator of DC function. DC-specific deletion of Tbk1 causes T cell activation and autoimmune symptoms and also enhances antitumor immunity in animal models of cancer immunotherapy. The TBK1-deficient DCs have up-regulated expression of co-stimulatory molecules and increased T cell-priming activity. We further demonstrate that TBK1 negatively regulates the induction of a subset of genes by type I interferon receptor (IFNAR). Deletion of IFNAR1 could largely prevent aberrant T cell activation and autoimmunity in DC-conditional Tbk1 knockout mice. These findings identify a DC-specific function of TBK1 in the maintenance of immune homeostasis and tolerance. © 2017 Xiao et al.

  13. Splenectomy inhibits non-small cell lung cancer growth by modulating anti-tumor adaptive and innate immune response

    Science.gov (United States)

    Levy, Liran; Mishalian, Inbal; Bayuch, Rachel; Zolotarov, Lida; Michaeli, Janna; Fridlender, Zvi G

    2015-01-01

    It has been shown that inhibitors of the immune system reside in the spleen and inhibit the endogenous antitumor effects of the immune system. We hypothesized that splenectomy would inhibit the growth of relatively large non-small lung cancer (NSCLC) tumors by modulating the systemic inhibition of the immune system, and in particular Myeloid Derived Suppressor Cells (MDSC). The effect of splenectomy was evaluated in several murine lung cancer models. We found that splenectomy reduces tumor growth and the development of lung metastases, but only in advanced tumors. In immune-deficient NOD-SCID mice the effect of splenectomy on tumor growth and metastatic spread disappeared. Splenectomy significantly reduced the presence of MDSC, and especially monocytic-MDSC in the circulation and inside the tumor. Specific reduction of the CCR2+ subset of monocytic MDSC was demonstrated, and the importance of the CCL2-CCR2 axis was further shown by a marked reduction in CCL2 following splenectomy. These changes were followed by changes in the macrophages contents of the tumors to become more antitumorigenic, and by increased activation of CD8+ Cytotoxic T-cells (CTL). By MDSC depletion, and adoptive transfer of MDSCs, we demonstrated that the effect of splenectomy on tumor growth was substantially mediated by MDSC cells. We conclude that the spleen is an important contributor to tumor growth and metastases, and that splenectomy can blunt this effect by depletion of MDSC, changing the amount and characteristics of myeloid cells and enhancing activation of CTL. PMID:26137413

  14. Abscopal antitumor immune effects of magnet-mediated hyperthermia at a high therapeutic temperature on Walker-256 carcinosarcomas in rats.

    Science.gov (United States)

    Wang, Hui; Zhang, Li; Shi, Yingrui; Javidiparsijani, Sara; Wang, Guirong; Li, Xiao; Ouyang, Weiwei; Zhou, Jumei; Zhao, Lingyun; Wang, Xiaowen; Zhang, Xiaodong; Gao, Fuping; Liu, Jingshi; Luo, Junming; Tang, Jintian

    2014-03-01

    The abscopal effect has previously been described in various tumors and is associated with radiation therapy and hyperthermia, with possible underlying mechanisms explaining each observed case. In the present study, we aimed to investigate the antitumor effects of magnet-mediated hyperthermia on Walker-256 carcinosarcomas in rats at two different temperature ranges (42-46°C and 50-55°C). We also aimed to identify whether a higher therapeutic temperature of magnetic-mediated hyperthermia improves the abscopal antitumor effects, where localised irradiation of the tumor causes not only the irradiated tumor to shrink, but also tumors located far from the area of irradiation. Following induction of carcinosarcoma in both sides of the body, magnet-mediated hyperthermia was applied to one side only, leaving the other side as a control. The changes in tumor growth were observed. Our results demonstrated that magnet-mediated hyperthermia at a higher temperature inhibited the growth of carcinosarcoma at the site of treatment. Furthermore, the growth of the carcinosarcoma on the untreated side was also inhibited. The expression levels of proliferating cell nuclear antigen were decreased in the hyperthermia group, which was more significant in the higher temperature test group. Flow cytometric analysis showed an increased number of CD4- and CD8-positive T cells, and enzyme-linked immunosorbent assay showed increased levels of interferon-γ and interleukin-2 in the higher temperature group. These results suggested that magnet-mediated hyperthermia at a higher temperature (50-55°C) can improve the abscopal antitumor effects and stimulate a greater endogenous immune response in carcinosarcoma-bearing rats.

  15. The role of immune system exhaustion on cancer cell escape and anti-tumor immune induction after irradiation.

    Science.gov (United States)

    Mendes, Fernando; Domingues, Cátia; Rodrigues-Santos, Paulo; Abrantes, Ana Margarida; Gonçalves, Ana Cristina; Estrela, Jéssica; Encarnação, João; Pires, Ana Salomé; Laranjo, Mafalda; Alves, Vera; Teixo, Ricardo; Sarmento, Ana Bela; Botelho, Maria Filomena; Rosa, Manuel Santos

    2016-04-01

    Immune surveillance seems to represent an effective tumor suppressor mechanism. However, some cancer cells survive and become variants, being poorly immunogenic and able to enter a steady-state phase. These cells become functionally dormant or remain hidden clinically throughout. Neoplastic cells seem to be able to instruct immune cells to undergo changes promoting malignancy. Radiotherapy may act as a trigger of the immune response. After radiotherapy a sequence of reactions occurs, starting in the damage of oncogenic cells by multiple mechanisms, leading to the immune system positive feedback against the tumor. The link between radiotherapy and the immune system is evident. T cells, macrophages, Natural Killer cells and other immune cells seem to have a key role in controlling the tumor. T cells may be dysfunctional and remain in a state of T cell exhaustion, nonetheless, they often retain a high potential for successful defense against cancer, being able to be mobilized to become highly functional. The lack of clinical trials on a large scale makes data a little robust, in spite of promising information, there are still many variables in the studies relating to radiation and immune system. The clarification of the mechanisms underlying immune response to radiation exposure may contribute to treatment improvement, gain of life quality and span of patients. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. Synergistic effect of CTLA-4 blockade and cancer chemotherapy in the induction of anti-tumor immunity.

    Directory of Open Access Journals (Sweden)

    W Joost Lesterhuis

    Full Text Available Several chemotherapeutics exert immunomodulatory effects. One of these is the nucleoside analogue gemcitabine, which is widely used in patients with lung cancer, ovarian cancer, breast cancer, mesothelioma and several other types of cancer, but with limited efficacy. We hypothesized that the immunopotentiating effects of this drug are partly restrained by the inhibitory T cell molecule CTLA-4 and thus could be augmented by combining it with a blocking antibody against CTLA-4, which on its own has recently shown beneficial clinical effects in the treatment of patients with metastatic melanoma. Here we show, using two non-immunogenic murine tumor models, that treatment with gemcitabine chemotherapy in combination with CTLA-4 blockade results in the induction of a potent anti-tumor immune response. Depletion experiments demonstrated that both CD4(+ and CD8(+ T cells are required for optimal therapeutic effect. Mice treated with the combination exhibited tumor regression and long-term protective immunity. In addition, we show that the efficacy of the combination is moderated by the timing of administration of the two agents. Our results show that immune checkpoint blockade and cytotoxic chemotherapy can have a synergistic effect in the treatment of cancer. These results provide a basis to pursue combination therapies with anti-CTLA-4 and immunopotentiating chemotherapy and have important implications for future studies in cancer patients. Since both drugs are approved for use in patients our data can be immediately translated into clinical trials.

  17. EpCAM peptide-primed dendritic cell vaccination confers significant anti-tumor immunity in hepatocellular carcinoma cells.

    Directory of Open Access Journals (Sweden)

    Yoo Jin Choi

    Full Text Available Cancer stem-like cells (CSCs may play a key role in tumor initiation, self-renewal, differentiation, and resistance to current treatments. Dendritic cells (DCs play a vital role in host immune reactions as well as antigen presentation. In this study, we explored the suitability of using CSC peptides as antigen sources for DC vaccination against human breast cancer and hepatocellular carcinoma (HCC with the aim of achieving CSC targeting and enhancing anti-tumor immunity. CD44 is used as a CSC marker for breast cancer and EpCAM is used as a CSC marker for HCC. We selected CD44 and EpCAM peptides that bind to HLA-A2 molecules on the basis of their binding affinity, as determined by a peptide-T2 binding assay. Our data showed that CSCs express high levels of tumor-associated antigens (TAAs as well as major histocompatibility complex (MHC molecules. Pulsing DCs with CD44 and EpCAM peptides resulted in the efficient generation of mature DCs (mDCs, thus enhancing T cell stimulation and generating potent cytotoxic T lymphocytes (CTLs. The activation of CSC peptide-specific immune responses by the DC vaccine in combination with standard chemotherapy may provide better clinical outcomes in advanced carcinomas.

  18. Pretreatment antigen-specific immunity and regulation - association with subsequent immune response to anti-tumor DNA vaccination.

    Science.gov (United States)

    Johnson, Laura E; Olson, Brian M; McNeel, Douglas G

    2017-07-18

    Immunotherapies have demonstrated clinical benefit for many types of cancers, however many patients do not respond, and treatment-related adverse effects can be severe. Hence many efforts are underway to identify treatment predictive biomarkers. We have reported the results of two phase I trials using a DNA vaccine encoding prostatic acid phosphatase (PAP) in patients with biochemically recurrent prostate cancer. In both trials, persistent PAP-specific Th1 immunity developed in some patients, and this was associated with favorable changes in serum PSA kinetics. In the current study, we sought to determine if measures of antigen-specific or antigen non-specific immunity were present prior to treatment, and associated with subsequent immune response, to identify possible predictive immune biomarkers. Patients who developed persistent PAP-specific, IFNγ-secreting immune responses were defined as immune "responders." The frequency of peripheral T cell and B cell lymphocytes, natural killer cells, monocytes, dendritic cells, myeloid derived suppressor cells, and regulatory T cells were assessed by flow cytometry and clinical laboratory values. PAP-specific immune responses were evaluated by cytokine secretion in vitro, and by antigen-specific suppression of delayed-type hypersensitivity to a recall antigen in an in vivo SCID mouse model. The frequency of peripheral blood cell types did not differ between the immune responder and non-responder groups. Non-responder patients tended to have higher PAP-specific IL-10 production pre-vaccination (p = 0.09). Responder patients had greater preexisting PAP-specific bystander regulatory responses that suppressed DTH to a recall antigen (p = 0.016). While our study population was small (n = 38), these results suggest that different measures of antigen-specific tolerance or regulation might help predict immunological outcome from DNA vaccination. These will be prospectively evaluated in an ongoing randomized, phase II trial.

  19. T-regulatory cells depletion is the main cause for enhanced antitumor immunity during radio-sensitization of tumors by 2-deoxy-D-glucose

    International Nuclear Information System (INIS)

    Farooque, Abdullah; Verma, Amit; Singh, Niharika; Chauhan, Sachin Kumar Singh; Jethani, Jyoti; Adhikari, J.S.; Dwarakanath, B.S.; Afrin, Farhat

    2014-01-01

    Regulatory T cells (Tregs) are known to have profound effects in blocking anti-tumor immunity. Therefore, Tregs are seen as a major hurdle that must be overcome in order to improve the efficacy of cancer therapy. The glycolytic inhibitor, 2-deoxy-d-glucose (2-DG) enhances radiation and chemotherapeutics induced death of many cancer cells in vitro and local tumor control in vivo, which was found to be associated with the enhanced anti-tumor immunity. Therefore, we investigated the role of Tregs in determining the tumor response to the combined treatment of 2-DG plus ionizing radiation. Ehrlich ascites tumor bearing mice were administered with a single dose of 2-DG (2 gm/Kg/b.wt) intravenously just before focal irradiation (10 Gy). Immuno-phenotyping of Tregs in secondary lymphoid organs was carried out using flow cytometry, while related cytokines were analyzed using bead array and ELISA. Further, mRNA and protein levels of transcription factors were assessed in sorted splenic CD4 + cells and CD4 + CD25 + using real time PCR and Western blot techniques. Results clearly showed depletion (TRAIL mediated apoptosis) of T regs (CD4 + CD25 + FoxP3 + CD39 + FR4 + GITR + CD127 - ), in blood, spleen, lymph node and tumor following the combined treatment. This led to the immune activation in the periphery, secondary lymphoid organs and massive infiltration of CD4 + , CD8 + and NK cells in the tumor, which correlated well with the complete response (cure; tumor free survival). Association of Treg depletion with the tumor response was further confirmed using low doses of cyclophosphamide (which depletes Tegs) and rapamycin (activator of Tregs),wherein the depletor of Tregs enhanced the efficacy of combined treatment, while Tregs enhancer compromised the efficacy. These studies unequivocally established the role of Tregs in determining the therapeutic response and can be used as a target for enhancing the efficacy of this combined treatment, besides establishing the potential of

  20. MUC1 and survivin combination tumor gene vaccine generates specific immune responses and anti-tumor effects in a murine melanoma model.

    Science.gov (United States)

    Zhang, Haihong; Liu, Chenlu; Zhang, Fangfang; Geng, Fei; Xia, Qiu; Lu, Zhenzhen; Xu, Ping; Xie, Yu; Wu, Hui; Yu, Bin; Wu, Jiaxin; Yu, Xianghui; Kong, Wei

    2016-05-23

    MUC1 and survivin are ideal tumor antigens. Although many cancer vaccines targeting survivin or MUC1 have entered clinical trials, no vaccine combining MUC1 and survivin have been reported. Due to tumor heterogeneity, vaccines containing a combination of antigens may have improved efficacy and coverage of a broader spectrum of cancer targets. Here, cellular responses and anti-tumor activities induced by a combination of DNA vaccine targeting MUC1 and survivin (MS) were evaluated. Results showed that CTL activity and inhibition of tumor growth were obviously enhanced in mice immunized with the combined vaccine in a protection assay. However, in order to enhance the therapeutic effect in the treatment assay, a recombinant adenovirus (rAd) vaccine expressing MUC1 and survivin (Ad-MS) was used as a booster following the DNA vaccine prime. Meanwhile, IL-2 promoting T cell proliferation was used as an immunoadjuvant for the DNA vaccine. Results showed that the CTL activity response to the DNA vaccine was enhanced nearly 200% when boosted by the rAd vaccine and was further enhanced by nearly 60% when combined with the IL-2 adjuvant. Therefore, DNA prime combined with rAd boost and IL-2 (MS/IL2/Ad-MS) adjuvant was considered as the best strategy and further evaluated. Multiple cytokines promoting cellular immune responses were shown to be greatly enhanced in mice immunized with MS/IL2/Ad-MS. Moreover, in the treatment assay, the tumor inhibition rate of MS/IL2/Ad-MS reached up to 50.1%, which may be attributed to the enhancement of immune responses and reduction of immunosuppressive factors in tumor-bearing mice. These results suggested that immunization with the combination vaccine targeting MUC1 and survivin using a DNA prime-rAd boost strategy along with IL-2 adjuvant may be an effective method for breaking through immune tolerance to tumors expressing these antigens with potential therapeutic benefits in melanoma cancer. Copyright © 2016. Published by Elsevier Ltd.

  1. Enavatuzumab, a Humanized Anti-TWEAK Receptor Monoclonal Antibody, Exerts Antitumor Activity through Attracting and Activating Innate Immune Effector Cells

    Directory of Open Access Journals (Sweden)

    Shiming Ye

    2017-01-01

    Full Text Available Enavatuzumab is a humanized IgG1 anti-TWEAK receptor monoclonal antibody that was evaluated in a phase I clinical study for the treatment of solid malignancies. The current study was to determine whether and how myeloid effector cells were involved in postulated mechanisms for its potent antitumor activity in xenograft models. The initial evidence for a role of effector cells was obtained in a subset of tumor xenograft mouse models whose response to enavatuzumab relied on the binding of Fc of the antibody to Fcγ receptor. The involvement of effector cells was further confirmed by immunohistochemistry, which revealed strong infiltration of CD45+ effector cells into tumor xenografts in responding models, but minimal infiltration in nonresponders. Consistent with the xenograft studies, human effector cells preferentially migrated toward in vivo-responsive tumor cells treated by enavatuzumab in vitro, with the majority of migratory cells being monocytes. Conditioned media from enavatuzumab-treated tumor cells contained elevated levels of chemokines, which might be responsible for enavatuzumab-triggered effector cell migration. These preclinical studies demonstrate that enavatuzumab can exert its potent antitumor activity by actively recruiting and activating myeloid effectors to kill tumor cells. Enavatuzumab-induced chemokines warrant further evaluation in clinical studies as potential biomarkers for such activity.

  2. Injury-induced immune responses in Hydra.

    Science.gov (United States)

    Wenger, Yvan; Buzgariu, Wanda; Reiter, Silke; Galliot, Brigitte

    2014-08-01

    The impact of injury-induced immune responses on animal regenerative processes is highly variable, positive or negative depending on the context. This likely reflects the complexity of the innate immune system that behaves as a sentinel in the transition from injury to regeneration. Early-branching invertebrates with high regenerative potential as Hydra provide a unique framework to dissect how injury-induced immune responses impact regeneration. A series of early cellular events likely require an efficient immune response after amputation, as antimicrobial defence, epithelial cell stretching for wound closure, migration of interstitial progenitors toward the wound, cell death, phagocytosis of cell debris, or reconstruction of the extracellular matrix. The analysis of the injury-induced transcriptomic modulations of 2636 genes annotated as immune genes in Hydra identified 43 genes showing an immediate/early pulse regulation in all regenerative contexts examined. These regulations point to an enhanced cytoprotection via ROS signaling (Nrf, C/EBP, p62/SQSMT1-l2), TNFR and TLR signaling (TNFR16-like, TRAF2l, TRAF5l, jun, fos-related, SIK2, ATF1/CREB, LRRC28, LRRC40, LRRK2), proteasomal activity (p62/SQSMT1-l1, Ced6/Gulf, NEDD8-conjugating enzyme Ubc12), stress proteins (CRYAB1, CRYAB2, HSP16.2, DnaJB9, HSP90a1), all potentially regulating NF-κB activity. Other genes encoding immune-annotated proteins such as NPYR4, GTPases, Swap70, the antiproliferative BTG1, enzymes involved in lipid metabolism (5-lipoxygenase, ACSF4), secreted clotting factors, secreted peptidases are also pulse regulated upon bisection. By contrast, metalloproteinases and antimicrobial peptide genes largely follow a context-dependent regulation, whereas the protease inhibitor α2macroglobulin gene exhibits a sustained up-regulation. Hence a complex immune response to injury is linked to wound healing and regeneration in Hydra. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights

  3. The effect of polyanhydride chemistry in particle-based cancer vaccines on the magnitude of the anti-tumor immune response.

    Science.gov (United States)

    Wafa, Emad I; Geary, Sean M; Goodman, Jonathan T; Narasimhan, Balaji; Salem, Aliasger K

    2017-03-01

    The goal of this research was to study the effect of polyanhydride chemistry on the immune response induced by a prophylactic cancer vaccine based on biodegradable polyanhydride particles. To achieve this goal, different compositions of polyanhydride copolymers based on 1,8-bis-(p-carboxyphenoxy)-3,6-dioxaoctane (CPTEG), 1,6-bis-(p-carboxyphenoxy)-hexane (CPH), and sebacic anhydride (SA) were synthesized by melt polycondensation, and polyanhydride copolymer particles encapsulating a model antigen, ovalbumin (OVA), were then synthesized using a double emulsion solvent evaporation technique. The ability of three different compositions of polyanhydride copolymers (50:50 CPTEG:CPH, 20:80 CPTEG:CPH, and 20:80 CPH:SA) encapsulating OVA to elicit immune responses was investigated. In addition, the impact of unmethylated oligodeoxynucleotides containing deoxycytidyl-deoxyguanosine dinucleotides (CpG ODN), an immunological adjuvant, on the immune response was also studied. The immune response to cancer vaccines was measured after treatment of C57BL/6J mice with two subcutaneous injections, seven days apart, of 50μg OVA encapsulated in particles composed of different polyanhydride copolymers with or without 25μg CpG ODN. In vivo studies showed that 20:80 CPTEG:CPH particles encapsulating OVA significantly stimulated the highest level of CD8 + T lymphocytes, generated the highest serum titers of OVA-specific IgG antibodies, and provided longer protection against tumor challenge with an OVA-expressing thymoma cell line in comparison to formulations made from other polyanhydride copolymers. The results also revealed that vaccination with CpG ODN along with polyanhydride particles encapsulating OVA did not enhance the immunogenicity of OVA. These results accentuate the crucial role of the copolymer composition of polyanhydrides in stimulating the immune response and provide important insights on rationally designing efficacious cancer vaccines. Compared to soluble cancer

  4. Vaccination with Irradiated Tumor Cells Engineered to Secrete Murine Granulocyte-Macrophage Colony-Stimulating Factor Stimulates Potent, Specific, and Long-Lasting Anti-Tumor Immunity

    Science.gov (United States)

    Dranoff, Glenn; Jaffee, Elizabeth; Lazenby, Audrey; Golumbek, Paul; Levitsky, Hyam; Brose, Katja; Jackson, Valerie; Hamada, Hirofumi; Pardoll, Drew; Mulligan, Richard C.

    1993-04-01

    To compare the ability of different cytokines and other molecules to enhance the immunogenicity of tumor cells, we generated 10 retroviruses encoding potential immunomodulators and studied the vaccination properties of murine tumor cells transduced by the viruses. Using a B16 melanoma model, in which irradiated tumor cells alone do not stimulate significant anti-tumor immunity, we found that irradiated tumor cells expressing murine granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulated potent, long-lasting, and specific anti-tumor immunity, requiring both CD4^+ and CD8^+ cells. Irradiated cells expressing interleukins 4 and 6 also stimulated detectable, but weaker, activity. In contrast to the B16 system, we found that in a number of other tumor models, the levels of anti-tumor immunity reported previously in cytokine gene transfer studies involving live, transduced cells could be achieved through the use of irradiated cells alone. Nevertheless, manipulation of the vaccine or challenge doses made it possible to demonstrate the activity of murine GM-CSF in those systems as well. Overall, our results have important implications for the clinical use of genetically modified tumor cells as therapeutic cancer vaccines.

  5. Trypanosoma cruzi extracts elicit protective immune response against chemically induced colon and mammary cancers.

    Science.gov (United States)

    Ubillos, Luis; Freire, Teresa; Berriel, Edgardo; Chiribao, María Laura; Chiale, Carolina; Festari, María Florencia; Medeiros, Andrea; Mazal, Daniel; Rondán, Mariella; Bollati-Fogolín, Mariela; Rabinovich, Gabriel A; Robello, Carlos; Osinaga, Eduardo

    2016-04-01

    Trypanosoma cruzi, the protozoan parasite that causes Chagas' disease, has anticancer effects mediated, at least in part, by parasite-derived products which inhibit growth of tumor cells. We investigated whether immunity to T. cruzi antigens could induce antitumor activity, using two rat models which reproduce human carcinogenesis: colon cancer induced by 1,2-dimethylhydrazine (DMH), and mammary cancer induced by N-nitroso-N-methylurea (NMU). We found that vaccination with T. cruzi epimastigote lysates strongly inhibits tumor development in both animal models. Rats immunized with T. cruzi antigens induce activation of both CD4(+) and CD8(+) T cells and splenocytes from these animals showed higher cytotoxic responses against tumors as compared to rats receiving adjuvant alone. Tumor-associated immune responses included increasing number of CD11b/c(+) His48(-) MHC II(+) cells corresponding to macrophages and/or dendritic cells, which exhibited augmented NADPH-oxidase activity. We also found that T. cruzi lysate vaccination developed antibodies specific for colon and mammary rat cancer cells, which were capable of mediating antibody-dependent cellular cytotoxicity (ADCC) in vitro. Anti-T. cruzi antibodies cross-reacted with human colon and breast cancer cell lines and recognized 41/60 (68%) colon cancer and 38/63 (60%) breast cancer samples in a series of 123 human tumors. Our results suggest that T. cruzi antigens can evoke an integrated antitumor response involving both the cellular and humoral components of the immune response and provide novel insights into the understanding of the intricate relationship between parasite infection and tumor growth. © 2015 UICC.

  6. Murine Dendritic Cells Pulsed with Whole Tumor Lysates Mediate Potent Antitumor Immune Responses in vitro and in vivo

    Science.gov (United States)

    Fields, R. C.; Shimizu, K.; Mule, J. J.

    1998-08-01

    The highly efficient nature of dendritic cells (DC) as antigen-presenting cells raises the possibility of uncovering in tumor-bearing hosts very low levels of T cell reactivity to poorly immunogenic tumors that are virtually undetectable by other means. Here, we demonstrate the in vitro and in vivo capacities of murine bone marrow-derived, cytokine-driven DC to elicit potent and specific anti-tumor responses when pulsed with whole tumor lysates. Stimulation of naive spleen-derived T cells by tumor lysate-pulsed DC generated tumor-specific proliferative cytokine release and cytolytic reactivities in vitro. In addition, in two separate strains of mice with histologically distinct tumors, s.c. injections of DC pulsed with whole tumor lysates effectively primed these animals to reject subsequent lethal challenges with viable parental tumor cells and, important to note, also mediated significant reductions in the number of metastases established in the lungs. Tumor rejection depended on host-derived CD8+ T cells and, to a lesser extent, CD4+ T cells. Spleens from mice that had rejected their tumors contained specific precursor cytotoxic T lymphocytes. The use of whole tumor lysates as a source of tumor-associated antigen(s) for pulsing of DC circumvents several limitations encountered with other methods as well as provides certain distinct advantages, which are discussed. These data serve as rationale for our recent initiation of a phase I clinical trial of immunization with autologous tumor lysate-pulsed DC in adult and pediatric cancer patients.

  7. Depletion of regulatory T lymphocytes reverses the imbalance between pro- and anti-tumor immunities via enhancing antigen-specific T cell immune responses.

    Directory of Open Access Journals (Sweden)

    Yu-Li Chen

    Full Text Available BACKGROUND: The regulatory T cells (Tregs can actively suppress the immune responses. However, literature about detailed changes of host effective and suppressive immunities before and after depletion of Tregs in ovarian carcinomas, is rare. MATERIALS AND METHODS: Ovarian cancer patients and the ascitogenic animal model were employed. Immunologic profiles with flow cytometric analyses, immunohistochemistric staining, RT-PCR, ELISA, and ELISPOT assays were performed. In vivo depletion of Treg cells with the mAb PC61was also performed in the animal model. RESULTS: The cytokines, including IL-4 (p=0.017 and TNF-α (p=0.046, significantly decreased while others such as TGF-β (p=0.013, IL-6 (p=0.016, and IL-10 (p=0.018 were elevated in ascites of ovarian cancer patients, when the disease progressed to advanced stages. The ratio of CD8(+ T cell/Treg cell in ascites was also lower in advanced diseases than in early diseases (advanced 7.37 ± 0.64 vs. early 14.25 ± 3.11, p=0.037. The kinetic low-dose CD25 Ab depletion group had significantly lower intra-peritoneal tumor weight (0.20 ± 0.03 g than the sequential high-dose (0.69 ± 0.06 g and sequential low-dose (0.67 ± 0.07 g CD25 Ab deletion groups (p=0.001 after 49 days of tumor challenge in the animal. The kinetic low-dose CD25 Ab depletion group generated the highest number of IFN-γ-secreting, mesothelin-specific T lymphocytes compared to the other groups (p<0.001. CONCLUSIONS: The imbalance between effective and suppressive immunities becomes more severe as a tumor progresses. The depletion of Treg cells can correct the imbalance of immunologic profiles and generate potent anti-tumor effects. Targeting Treg cells can be a new strategy for the immunotherapy of ovarian carcinoma.

  8. Dendritic cells loaded with HeLa-derived exosomes simulate an antitumor immune response.

    Science.gov (United States)

    Ren, Guoping; Wang, Yanhong; Yuan, Shexia; Wang, Baolian

    2018-05-01

    The aim of the present study was to investigate the effect of loading dendritic cells (DCs) with HeLa-derived exosomes on cytotoxic T-lymphocyte (CTL) responses, and the cytotoxic effects of CTL responses on the HeLa cell line. Ultrafiltration centrifugation combined with sucrose density gradient ultracentrifugation was applied to isolate exosomes (HeLa-exo) from the supernatant of HeLa cells. Morphological features of HeLa-exo were identified by transmission electron microscopy (TEM), and the expression of cluster of differentiation (CD)63 was detected by western blotting. Next, monocytes were isolated from peripheral blood and cultured with the removal of adherent cells to induce DC proliferation. DCs were then phenotypically characterized by flow cytometry. Finally, MTT assays were performed to analyze the effects of DCs loaded with HeLa-exo on T cell proliferation and cytotoxicity assays to evaluate the effect of CTL responses on HeLa cells. TEM revealed that HeLa-exo exhibit typical cup-shaped morphology with a diameter range of 30-100 nm. It was also identified that the CD63 surface antigen is expressed on HeLa-exo. Furthermore, monocyte-derived DCs were able to express CD1a, suggesting that DC induction was a success. DCs exhibited hair-like protrusions and other typical dendritic cell morphology. Furthermore, DCs loaded with HeLa-exo could enhance CTL proliferation and the cytotoxic activity of CTLs compared with DCs without HeLa-exo (PHeLa-exo may promote T cell proliferation and induce CTL responses to inhibit the growth of cervical cancer cells in vitro .

  9. Aqueous extract of Sapindus mukorossi induced cell death of A549 cells and exhibited antitumor property in vivo.

    Science.gov (United States)

    Liu, Min; Chen, Yen-Lin; Kuo, Yao-Haur; Lu, Mei-Kuang; Liao, Chia-Ching

    2018-03-19

    Sapindus mukorossi is a deciduous plant and has recently been recognized to have anticancer property. In the present study, we discovered that S. mukorossi leaf and stem aqueous extract (SaM) contained two polysaccharides mainly made of myo-inositol, galactose, glucose, and fructose and the aim of this study was to investigate the antitumor property the aqueous extract SaM. In vitro treatment of SaM diminished proliferative potential of lung adenocarcinomic cells and induced intracellular oxidative stress, as well as necrotic cell death. Moreover, exposure to SaM attenuated cell migration, demonstrating the effectiveness at reducing invasive property of malignant lung cells. Gene and protein expression studies indicated that SaM treatment altered the expression of proliferation/survival modulator NF-κB, tumor growth modulator ERK2, metastasis-associated molecules MMP9/12, and tumor suppressor p53 in A549 cells. Using model animals bearing Lewis lung cancer cell LL/2, we demonstrated that SaM was antitumoral and did not induce any undesired organ damage, immunotoxicity, and off-target inflammation. This work, to our knowledge, is the first study documents the antitumor bioactivity of aqueous extract riched in polysaccharides from S. mukorossi and provides insights into the potential pharmacological application of SaM as antitumor agent against lung cancer.

  10. Surgical Stress Abrogates Pre-Existing Protective T Cell Mediated Anti-Tumor Immunity Leading to Postoperative Cancer Recurrence.

    Directory of Open Access Journals (Sweden)

    Abhirami A Ananth

    Full Text Available Anti-tumor CD8+ T cells are a key determinant for overall survival in patients following surgical resection for solid malignancies. Using a mouse model of cancer vaccination (adenovirus expressing melanoma tumor-associated antigen (TAA-dopachrome tautomerase (AdDCT and resection resulting in major surgical stress (abdominal nephrectomy, we demonstrate that surgical stress results in a reduction in the number of CD8+ T cell that produce cytokines (IFNγ, TNFα, Granzyme B in response to TAA. This effect is secondary to both reduced proliferation and impaired T cell function following antigen binding. In a prophylactic model, surgical stress completely abrogates tumor protection conferred by vaccination in the immediate postoperative period. In a clinically relevant surgical resection model, vaccinated mice undergoing a positive margin resection with surgical stress had decreased survival compared to mice with positive margin resection alone. Preoperative immunotherapy with IFNα significantly extends survival in surgically stressed mice. Importantly, myeloid derived suppressor cell (MDSC population numbers and functional impairment of TAA-specific CD8+ T cell were altered in surgically stressed mice. Our observations suggest that cancer progression may result from surgery-induced suppression of tumor-specific CD8+ T cells. Preoperative immunotherapies aimed at targeting the prometastatic effects of cancer surgery will reduce recurrence and improve survival in cancer surgery patients.

  11. A sesquiterpenelactone from Inula britannica induces anti-tumor effects dependent on Bcl-2 phosphorylation.

    Science.gov (United States)

    Rafi, Mohamed M; Bai, Nai-Sheng; Chi-Tang-Ho; Rosen, Robert T; White, Eileen; Perez, Denise; Dipaola, Robert S

    2005-01-01

    The over-expression of the anti-apoptotic protein Bcl-2 in cancer is associated with resistance to chemotherapeutic drugs. The phosphorylation of Bcl-2 is one mechanism by which anti-microtubule agents, such as paclitaxel or docetaxel, may inactivate Bcl-2. Although initially active in clinical studies, current anti-microtubule agents are only temporarily effective and the discovery of new agents is warranted. We isolated and identified two known sesquiterpenelactones, O, O-diacetylbritannilactone (OODABL) and O-acetylbritaanilactone (OABL) from the flowers of the medicinal plant Inula britannica and studied their mechanism of anti-tumor effects. To determine the biological significance of Bcl-2 phosphorylation, we used a baby rat kidney (BRK-p53) cell line that was transformed with EIA and a temperature-sensitive mutant p53. The BRK-p53 cell line was transfected with either a vector with wild type Bcl-2 or a vector in which Bcl-2 had mutations in the paclitaxel phosphorylation sites (pcDNA3.1 V5/His Bcl-2 S70, 87A). OODABL and OABL induced phosphorylation of Bcl-2 in breast, ovary and prostate cancer cell lines and induced G2/M cell cycle arrest. Using the BRK cells with mutant Bcl-2 (BRK-Bcl-2-mt) and control (BRK-Bcl-2-wt), we found that OODABL induced phosphorylation of Bcl-2 at sites similar to paclitaxel. Phosphorylation of Bcl-2 was important for OODABL-induced cytotoxicity, since the abrogation of phosphorylation in BRK-Bcl-2-mt cells decreased OODABL-induced cytotoxicity. We concluded that OODABL is cytotoxic in multiple tumor cell lines, and the cytotoxicity is dependent, at least in part, on the phosphorylation of Bcl-2.

  12. Oral administration of human papillomavirus type 16 E7 displayed on Lactobacillus casei induces E7-specific antitumor effects in C57/BL6 mice.

    Science.gov (United States)

    Poo, Haryoung; Pyo, Hyun-Mi; Lee, Tae-Young; Yoon, Sun-Woo; Lee, Jong-Soo; Kim, Chul-Joong; Sung, Moon-Hee; Lee, Seung-Hoon

    2006-10-01

    The mounting of a specific immune response against the human papillomavirus type 16 E7 protein (HPV16 E7) is important for eradication of HPV16 E7-expressing cancer cells from the cervical mucosa. To induce a mucosal immune response by oral delivery of the E7 antigen, we expressed the HPV16 E7 antigen on the surface of Lactobacillus casei by employing a novel display system in which the poly-gamma-glutamic acid (gamma-PGA) synthetase complex A (PgsA) from Bacillus subtilis (chungkookjang) was used as an anchoring motif. After surface expression of the HPV16 E7 protein was confirmed by Western blot, flow cytometry and immunofluorescence microscopy, mice were orally inoculated with L. casei-PgsA-E7. E7-specific serum IgG and mucosal IgA productions were enhanced after oral administration and significantly enhanced after boosting. Systemic and local cellular immunities were significantly increased after boosting, as shown by increased counts of lymphocytes (SI = 9.7 +/- 1.8) and IFN-gamma secreting cells [510 +/- 86 spot-forming cells/10(6)cells] among splenocytes and increased IFN-gamma in supernatants of vaginal lymphocytes. Furthermore, in an E7-based mouse tumor model, animals receiving orally administered L. casei-PgsA-E7 showed reduced tumor size and increased survival rate versus mice receiving control (L. casei-PgsA) immunization. These results collectively indicate that the oral administration of E7 displayed on lactobacillus induces cellular immunity and antitumor effects in mice. Copyright 2006 Wiley-Liss, Inc.

  13. Opposite role of Bax and BCL-2 in the anti-tumoral responses of the immune system

    Directory of Open Access Journals (Sweden)

    Bougras Gwenola

    2004-08-01

    Full Text Available Abstract Background The relative role of anti apoptotic (i.e. Bcl-2 or pro-apoptotic (e.g. Bax proteins in tumor progression is still not completely understood. Methods The rat glioma cell line A15A5 was stably transfected with human Bcl-2 and Bax transgenes and the viability of theses cell lines was analyzed in vitro and in vivo. Results In vitro, the transfected cell lines (huBax A15A5 and huBcl-2 A15A5 exhibited different sensitivities toward apoptotic stimuli. huBax A15A5 cells were more sensitive and huBcl-2 A15A5 cells more resistant to apoptosis than mock-transfected A15A5 cells (pCMV A15A5. However, in vivo, in syngenic rat BDIX, these cell lines behaved differently, as no tumor growth was observed with huBax A15A5 cells while huBcl-2 A15A5 cells formed large tumors. The immune system appeared to be involved in the rejection of huBax A15A5 cells since i huBax A15A5 cells were tumorogenic in nude mice, ii an accumulation of CD8+ T-lymphocytes was observed at the site of injection of huBax A15A5 cells and iii BDIX rats, which had received huBax A15A5 cells developed an immune protection against pCMV A15A5 and huBcl-2 A15A5 cells. Conclusions We show that the expression of Bax and Bcl-2 controls the sensitivity of the cancer cells toward the immune system. This sensitization is most likely to be due to an increase in immune induced cell death and/or the amplification of an anti tumour immune response

  14. Immune response to UV-induced tumors: mediation of progressor tumor rejection by natural killer cells

    International Nuclear Information System (INIS)

    Streeter, P.R.; Fortner, G.W.

    1986-01-01

    Skin tumors induced in mice by chronic ultraviolet (UV) irradiation are highly antigenic and can induce a state of transplantation immunity in syngeneic animals. In the present study, the authors compared the in vitro cytolytic activity of splenic lymphocytes from mice immunized with either regressor or progressor UV-tumors. The results of this comparison implicated tumor-specific cytolytic T (Tc) lymphocytes in rejection of regressor UV-tumors, and revealed that immunization with the progressor UV-tumor 2237 failed to elicit detectable levels of progressor tumor-specific Tc cells even as the tumors rejected. Following in vitro resensitization of spleen cells from either regressor or progressor tumor immune animals, the authors found NK-like lymphocytes with anti-tumor activity. As the authors had not detected cells with this activity in splenic lymphocyte preparations prior to in vitro resensitization, the authors examined lymphocytes from the local tumor environment during the course of progressor tumor rejection for this activity. This analysis revealed NK lymphocytes exhibiting significant levels of cytolytic activity against UV-tumors. These results implicate NK cells as potential effector cells in the rejection of progressor UV-tumors by immune animals, and suggests that these cells may be regulated by T lymphocytes

  15. Drug-induced immune hemolytic anemia

    Science.gov (United States)

    Immune hemolytic anemia secondary to drugs; Anemia - immune hemolytic - secondary to drugs ... In some cases, a drug can cause the immune system to mistake your own red blood cells for foreign substances. The body responds by making ...

  16. Photo-Induced Antitumor Effect of 3,6-Bis(1-methyl-4-vinylpyridinium Carbazole Diiodide

    Directory of Open Access Journals (Sweden)

    Ya-Shuan Chou

    2013-01-01

    Full Text Available We have applied a fluorescent molecule 3,6-bis(1-methyl-4-vinylpyridinium carbazole diiodide (BMVC for tumor targeting and treatment. In this study, we investigated the photo-induced antitumor effect of BMVC. In vitro cell line studies showed that BMVC significantly killed TC-1 tumor cells at light dose greater than 40 J/cm2. The fluorescence of BMVC in the tumor peaked at 3 hours and then gradually decreased to reach the control level after 24 hours. In vivo tumor treatment studies showed BMVC plus light irradiation (iPDT significantly inhibited the tumor growth. At day 24 after tumor implantation, tumor volume was measured to be 225±79 mm3, 2542±181 mm3, 1533±766 mm3, and 1317±108 mm3 in the iPDT, control, light-only, and BMVC-only groups, respectively. Immunohistochemistry studies showed the microvascular density was significantly lower in the iPDT group. Taken together, our results demonstrated that BMVC may be a potent tumor-specific photosensitizer (PS for PDT.

  17. SEP enhanced the antitumor activity of 5-fluorouracil by up-regulating NKG2D/MICA and reversed immune suppression via inhibiting ROS and caspase-3 in mice.

    Science.gov (United States)

    Ke, Mengyun; Wang, Hui; Zhou, Yiran; Li, Jingwen; Liu, Yang; Zhang, Min; Dou, Jie; Xi, Tao; Shen, Baiyong; Zhou, Changlin

    2016-08-02

    Chemotherapy and immunotherapy are the main remedies used in cancer treatment. Because immunotherapy can not only reduce the toxicity of chemotherapeutics but also enhance antitumor effects in vivo, combining these two therapies is a trend that continues to gain more attention in clinic. SEP, a polysaccharide isolated from Strongylocentrotus nudus egg, has been reported to display antitumor activity by stimulating immune cells, including NK and T cells, via TLR2 and TLR4. In the present study, the synergistic effect between SEP and 5-fluorouracil (5-FU), a traditional cytotoxic drug, in vitro and in vivo was investigated. The results obtained indicated that SEP alone stimulated NK-92 cytotoxicity and coordinated with 5-FU to augment the cytotoxicity of NK-92 cells against HepG-2 or A549 cells in vitro. SEP promoted NK-92 activity by stimulating NKG2D and its downstream DAP10/PI3K/Erk signaling pathway. Additionally, 5-FU could increase MICA expression on HepG-2 or A549 cells and prevent membrane MICA from shedding as soluble MICA, which were abrogated in the tumor cells transfected with ADAM 10 overexpression plasmid. Moreover, in H22- or Lewis lung cancer (LLC)-bearing mouse models, SEP reversed 5-FU-induced atrophy and apoptosis in both the spleen and bone marrow in vivo by suppressing ROS generation and caspase-3 activation. All of these results highlight the potential for the combination of SEP and 5-FU in cancer therapy in the future.

  18. Radiofrequency ablation and immunostimulant OK-432: combination therapy enhances systemic antitumor immunity for treatment of VX2 lung tumors in rabbits.

    Science.gov (United States)

    Hamamoto, Shinichi; Okuma, Tomohisa; Yamamoto, Akira; Kageyama, Ken; Takeshita, Toru; Sakai, Yukimasa; Nishida, Norifumi; Matsuoka, Toshiyuki; Miki, Yukio

    2013-05-01

    To evaluate whether antitumor immunity is enhanced systemically by combining radiofrequency ablation (RFA) and local injection of an immunostimulant, OK-432. Experiments were approved by the institutional animal care committee. Experimental Japanese rabbits inoculated with VX2 tumors in the lung and the auricle were randomized into four groups of eight: control (supportive care), RFA (RFA of lung tumor), OK-432 (direct injection of OK-432 into lung tumor), and combination therapy (lung RFA and direct OK-432 injection into lung tumor). All procedures were performed 1 week after implantation of VX2 tumors (week 1). In addition, a VX2 tumor rechallenge test was performed in the RFA and combination therapy groups. Survival time was evaluated by means of the Kaplan-Meier method and by using the log-rank test for intergroup comparison. Mean auricle tumor volumes were calculated every week. Specific growth rates (SGRs) were calculated and compared by using the Mann-Whitney test. The median survival times of the control, RFA, OK-432, and combination therapy groups were 23, 36.5, 46.5, and 105 days, respectively. Survival was significantly prolonged in the combination therapy group when compared with the other three groups (P OK-432 may lead to indirectly activation of systemic antitumor immunity. © RSNA, 2013.

  19. A novel Smac mimetic APG-1387 demonstrates potent antitumor activity in nasopharyngeal carcinoma cells by inducing apoptosis.

    Science.gov (United States)

    Li, Ning; Feng, Lin; Han, Hui-Qiong; Yuan, Jing; Qi, Xue-Kang; Lian, Yi-Fan; Kuang, Bo-Hua; Zhang, Yu-Chen; Deng, Cheng-Cheng; Zhang, Hao-Jiong; Yao, You-Yuan; Xu, Miao; He, Gui-Ping; Zhao, Bing-Chun; Gao, Ling; Feng, Qi-Sheng; Chen, Li-Zhen; Yang, Lu; Yang, Dajun; Zeng, Yi-Xin

    2016-10-10

    Despite advances in the development of radiation against nasopharyngeal carcinoma (NPC), the management of advanced NPC remains a challenge. Smac mimetics are designed to neutralize inhibitor of apoptosis (IAP) proteins, thus reactivating the apoptotic program in cancer cells. In this study, we investigated the effect of a novel bivalent Smac mimetic APG-1387 in NPC. In vitro, APG-1387 in combination with TNF-α potently decreased NPC cell viability by inducing apoptosis in majority of NPC cell lines. The in vitro antitumor effect was RIPK1-dependent, whereas it was independent on IAPs, USP11, or EBV. Of note, the inhibition of NF-κB or AKT pathway rendered resistant NPC cells responsive to the treatment of APG-1387/TNF-α. In vivo, APG-1387 displayed antitumor activity as a single agent at well-tolerated doses, even in an in vitro resistant cell line. In summary, our results demonstrate that APG-1387 exerts a potent antitumor effect on NPC. These findings support clinical evaluation of APG-1387 as a potential treatment for advanced NPC. Copyright © 2016. Published by Elsevier Ireland Ltd.

  20. Changes of serum endocrine hormone levels in patients with cancerrelated fatigue and their correlation with anti-tumor immune response and tumor load

    Directory of Open Access Journals (Sweden)

    Lu Yang

    2017-08-01

    Full Text Available Objective: To study the changes of serum endocrine hormone levels in patients with cancerrelated fatigue (CRF and their correlation with anti-tumor immune response and tumor load. Methods: A total of 137 patients who were diagnosed with primary lung cancer in West China Hospital, Sichuan University between June 2014 and November 2016 were selected and then divided into CRF group and control group according to their self-reported symptoms, serum was collected to determine the levels of endocrine hormones and tumor markers, and peripheral blood was collected to detect the levels of immune cells. Results: Serum ACTH and TSH levels of CRF group were significantly higher than those of control group while Cor, FT3 and FT4 levels were significantly lower than those of control group; peripheral blood CD11b+ CD15 - CD33+ CD14+ M-MDSC, CD11b+ CD15-CD33+ CD14- G-MDSC, CD4+ CD25+ CD127lowTreg and CD19+ CD5+ CD1d+ Breg levels as well as serum CEA, Cyfra21-1, SCC-Ag, HE4, GDF- 15 and PCNA levels of CRF group were significantly higher than those of control group, positively correlated with serum ACTH and TSH levels, and negatively correlated with Cor, FT3 and FT4 levels. Conclusion: The changes of thyroid hormone and adrenal cortical hormone levels in patients with cancer-related fatigue are closely related to the inhibited antitumor immune response and increased tumor load.

  1. Tumor necrosis factor-α/CD40 ligand-engineered mesenchymal stem cells greatly enhanced the antitumor immune response and lifespan in mice.

    Science.gov (United States)

    Shahrokhi, Somayeh; Daneshmandi, Saeed; Menaa, Farid

    2014-03-01

    The interaction between mesenchymal stem cells (MSCs) and dendritic cells (DCs) affects T cell development and function. Further, the chemotactic capacity of MSCs, their interaction with the tumor microenvironment, and the intervention of immune-stimulatory molecules suggest possible exploitation of tumor necrosis factor-α (TNF-α) and CD40 ligand (CD40L) to genetically modify MSCs for enhanced cancer therapy. Both DCs and MSCs were isolated from BALB/c mice. DCs were then cocultured with MSCs transduced with TNF-α and/or CD40L [(TNF-α/CD40L)-MSCs]. Major DCs' maturation markers, DC and T cell cytokines such as interleukin-4, -6, -10, -12, TNF-α, tumor growth factor-β, as well as T cell proliferation, were assessed. Meantime, a BALB/c mouse breast tumor model was inducted by injecting 4T1 cells subcutaneously. Mice (n = 10) in each well-defined test groups (n = 13) were cotreated with DCs and/or (TNF-α/CD40L)-MSCs. The controls included untreated, empty vector-MSC, DC-lipopolysaccharide, and immature DC mouse groups. Eventually, cytokine levels from murine splenocytes, as well as tumor volume and survival of mice, were assessed. Compared with the corresponding controls, both in vitro and in vivo analyses showed induction of T helper 1 (Th1) as well as suppression of Th2 and Treg responses in test groups, which led to a valuable antitumor immune response. Further, the longest mouse survival was observed in mouse groups that were administered with DCs plus (TNF-α/CD40L)-MSCs. In our experimental setting, the present pioneered study demonstrates that concomitant genetic modification of MSCs with TNF-α and CD40L optimized the antitumor immunity response in the presence of DCs, meantime increasing the mouse lifespan.

  2. Effect of enteral immunonutrition after radical surgery for esophageal carcinoma on anti-tumor immune response and intestinal mucosal barrier function

    Directory of Open Access Journals (Sweden)

    Tong He

    2017-07-01

    Full Text Available Objective: To study the effect of enteral immunonutrition after radical surgery for esophageal carcinoma on anti-tumor immune response and intestinal mucosal barrier function. Methods: A total of 102 patients who received radical surgery for esophageal carcinoma in our hospital between May 2013 and December 2016 were selected and randomly divided into observation group and control group who received postoperative enteral immunonutrition and routine enteral nutrition respectively. 1 d before operation as well as 1 d and 7 d after operation, peripheral blood immune cell marker expression and serum intestinal mucosal barrier injury marker levels were detected. Results: 1 d after operation, peripheral blood T-bet, NKG2D, NKp30, NKp44 and NKp46 fluorescence intensity of both groups of patients were significantly lower than those 1d before operation while peripheral blood GATA-3 and Foxp3 fluorescence intensity as well as serum DAO, Occludin, ZO-1 and claudin-1 levels were significantly higher than those 1d before operation; peripheral blood T-bet, NKG2D, NKp30, NKp44 and NKp46 fluorescence intensity of observation group 7 d after operation were significantly higher than those 1 d after operation while peripheral blood GATA-3 and Foxp3 fluorescence intensity as well as serum DAO, Occludin, ZO-1 and claudin-1 levels were significantly lower than those 1 d after operation; peripheral blood T-bet, GATA-3, Foxp3, NKG2D, NKp30, NKp44 and NKp46 fluorescence intensity of control group 7 d after operation were not significant different from those 1 d after operation, and serum DAO, Occludin, ZO-1 and claudin-1 levels were significantly lower than those 1d after operation. Conclusion: Enteral immunonutrition after radical surgery for esophageal carcinoma can enhance the anti-tumor immune response and improve the intestinal mucosal barrier function.

  3. Abscopal antitumor immune effects of magnet-mediated hyperthermia at a high therapeutic temperature on Walker-256 carcinosarcomas in rats

    OpenAIRE

    WANG, HUI; ZHANG, LI; SHI, YINGRUI; JAVIDIPARSIJANI, SARA; WANG, GUIRONG; LI, XIAO; OUYANG, WEIWEI; ZHOU, JUMEI; ZHAO, LINGYUN; WANG, XIAOWEN; ZHANG, XIAODONG; GAO, FUPING; LIU, JINGSHI; LUO, JUNMING; TANG, JINTIAN

    2014-01-01

    The abscopal effect has previously been described in various tumors and is associated with radiation therapy and hyperthermia, with possible underlying mechanisms explaining each observed case. In the present study, we aimed to investigate the antitumor effects of magnet-mediated hyperthermia on Walker-256 carcinosarcomas in rats at two different temperature ranges (42–46°C and 50–55°C). We also aimed to identify whether a higher therapeutic temperature of magnetic-mediated hyperthermia impro...

  4. Inflammation promotes oral squamous carcinoma immune evasion via induced programmed death ligand-1 surface expression.

    Science.gov (United States)

    Lu, Wanlu; Lu, Libing; Feng, Yun; Chen, Jiao; Li, Yan; Kong, Xiangli; Chen, Sixiu; Li, Xiaoyu; Chen, Qianming; Zhang, Ping

    2013-05-01

    The association between inflammation and cancer provides a new target for tumor biotherapy. The inflammatory cells and molecules within the tumor microenvironment have decisive dual roles in antitumor immunity and immune evasion. In the present study, phytohemagglutinin (PHA) was used to stimulate peripheral blood mononuclear cells (PBMCs) to simulate the tumor inflammatory microenvironment. The effect of immune cells and inflammatory cytokines on the surface expression of programmed cell death-1 ligand 1 (PD-L1) and tumor immune evasion was investigated using flow cytometry (FCM) and an in vivo xenotransplantation model. Based on the data, PHA-activated, but not resting, immune cells were able to promote the surface expression of PD-L1 in Tca8113 oral squamous carcinoma cells via the secretion of inflammatory cytokines, but not by cell-cell contact. The majority of the inflammatory cytokines had no significant effect on the proliferation, cell cycle progression and apoptosis of the Tca8113 cells, although they each induced the expression of PD-L1 in a dose-dependent manner. In total, 99% of the Tca8113 cells expressed PD-L1 following treatment with the supernatant of PHA-stimulated PBMCs. The PHA-supernatant pretreated Tca8113 cells unusually induced Tca8113 antigen-specific CD8 + T cell apoptosis in vitro and the evasion of antigen-specific T cell attraction in a nude mouse tumor-bearing model. These results indicate a new mechanism for the promotion of tumor immune evasion by the tumor inflammatory microenvironment.

  5. Enriching the Housing Environment for Mice Enhances Their NK Cell Antitumor Immunity via Sympathetic Nerve-Dependent Regulation of NKG2D and CCR5.

    Science.gov (United States)

    Song, Yanfang; Gan, Yu; Wang, Qing; Meng, Zihong; Li, Guohua; Shen, Yuling; Wu, Yufeng; Li, Peiying; Yao, Ming; Gu, Jianren; Tu, Hong

    2017-04-01

    Mice housed in an enriched environment display a tumor-resistant phenotype due to eustress stimulation. However, the mechanisms underlying enriched environment-induced protection against cancers remain largely unexplained. In this study, we observed a significant antitumor effect induced by enriched environment in murine pancreatic cancer and lung cancer models. This effect remained intact in T/B lymphocyte-deficient Rag1 -/- mice, but was nearly eliminated in natural killer (NK) cell-deficient Beige mice or in antibody-mediated NK-cell-depleted mice, suggesting a predominant role of NK cells in enriched environment-induced tumor inhibition. Exposure to enriched environment enhanced NK-cell activity against tumors and promoted tumoral infiltration of NK cells. Enriched environment increased the expression levels of CCR5 and NKG2D (KLRK1) in NK cells; blocking their function effectively blunted the enriched environment-induced enhancement of tumoral infiltration and cytotoxic activity of NK cells. Moreover, blockade of β-adrenergic signaling or chemical sympathectomy abolished the effects of enriched environment on NK cells and attenuated the antitumor effect of enriched environment. Taken together, our results provide new insight into the mechanism by which eustress exerts a beneficial effect against cancer. Cancer Res; 77(7); 1611-22. ©2017 AACR . ©2017 American Association for Cancer Research.

  6. TTI-621 (SIRPαFc): A CD47-Blocking Innate Immune Checkpoint Inhibitor with Broad Antitumor Activity and Minimal Erythrocyte Binding.

    Science.gov (United States)

    Petrova, Penka S; Viller, Natasja Nielsen; Wong, Mark; Pang, Xinli; Lin, Gloria H Y; Dodge, Karen; Chai, Vien; Chen, Hui; Lee, Vivian; House, Violetta; Vigo, Noel T; Jin, Debbie; Mutukura, Tapfuma; Charbonneau, Marilyse; Truong, Tran; Viau, Stephane; Johnson, Lisa D; Linderoth, Emma; Sievers, Eric L; Maleki Vareki, Saman; Figueredo, Rene; Pampillo, Macarena; Koropatnick, James; Trudel, Suzanne; Mbong, Nathan; Jin, Liqing; Wang, Jean C Y; Uger, Robert A

    2017-02-15

    Purpose: The ubiquitously expressed transmembrane glycoprotein CD47 delivers an anti-phagocytic (do not eat) signal by binding signal-regulatory protein α (SIRPα) on macrophages. CD47 is overexpressed in cancer cells and its expression is associated with poor clinical outcomes. TTI-621 (SIRPαFc) is a fully human recombinant fusion protein that blocks the CD47-SIRPα axis by binding to human CD47 and enhancing phagocytosis of malignant cells. Blockade of this inhibitory axis using TTI-621 has emerged as a promising therapeutic strategy to promote tumor cell eradication. Experimental Design: The ability of TTI-621 to promote macrophage-mediated phagocytosis of human tumor cells was assessed using both confocal microscopy and flow cytometry. In vivo antitumor efficacy was evaluated in xenograft and syngeneic models and the role of the Fc region in antitumor activity was evaluated using SIRPαFc constructs with different Fc tails. Results: TTI-621 enhanced macrophage-mediated phagocytosis of both hematologic and solid tumor cells, while sparing normal cells. In vivo , TTI-621 effectively controlled the growth of aggressive AML and B lymphoma xenografts and was efficacious in a syngeneic B lymphoma model. The IgG1 Fc tail of TTI-621 plays a critical role in its antitumor activity, presumably by engaging activating Fcγ receptors on macrophages. Finally, TTI-621 exhibits minimal binding to human erythrocytes, thereby differentiating it from CD47 blocking antibodies. Conclusions: These data indicate that TTI-621 is active across a broad range of human tumors. These results further establish CD47 as a critical regulator of innate immune surveillance and form the basis for clinical development of TTI-621 in multiple oncology indications. Clin Cancer Res; 23(4); 1068-79. ©2016 AACR . ©2016 American Association for Cancer Research.

  7. Ceftriaxone-induced immune hemolytic anemia.

    Science.gov (United States)

    Neuman, Gal; Boodhan, Sabrina; Wurman, Ilana; Koren, Gideon; Bitnun, Ari; Kirby-Allen, Melanie; Ito, Shinya

    2014-12-01

    To describe a case of ceftriaxone-induced immune hemolytic anemia (CIIHA) in a 6 year-old boy with sickle cell disease (SCD) and perform a systematic literature review to delineate the clinical and laboratory features of this condition. EMBASE (1947-January 2014), MEDLINE (1946-January 2014), and databases from the US Food and Drug Administration and Health Canada were searched, using anemia, hemolytic anemia, hemolysis, and ceftriaxone as search terms. Additional references were identified from a review of literature citations. All case reports and observational studies describing clinical and laboratory features of CIIHA were included. A total of 37 eligible reports of CIIHA were identified, including our index case, and 70% were children. Mortality was 30% in all age groups and 64% in children. The majority of patients had underlying conditions (70%), of which SCD was most commonly reported. Previous ceftriaxone exposure was reported in 65%. Common features included elevated lactate dehydrogenase (70%); early, new-onset hemoglobinuria (59%); acute renal failure (46%); positive direct antibody testing (70%); and anticeftriaxone antibodies (68%). Also, 32% had a preceding, unrecognized, hemolytic episode associated with ceftriaxone. Given the common use of ceftriaxone worldwide, knowledge of CIIHA, which often goes undiagnosed until late in the course, is essential for clinicians. Based on the findings of this review, we suggest obtaining past history of ceftriaxone exposures and screening for new-onset hemoglobinuria during ceftriaxone therapy in selected patients as potential methods for early diagnosis of this rare but potentially fatal condition. © The Author(s) 2014.

  8. Anti-tumor activities of andrographolide, a diterpene from Andrographis paniculata, by inducing apoptosis and inhibiting VEGF level.

    Science.gov (United States)

    Zhao, Feng; He, En-Qi; Wang, Lu; Liu, Ke

    2008-01-01

    Andrographolide (1), a diterpenoid lactone isolated from a traditional herb (Andrographis paniculata), is known to possess potent anti-inflammatory activity. In this study, we investigated the anti-tumor effect of 1 on various cancer cell lines in vitro. It induced apoptosis of prostate cancer (PC-3) cells (the most sensitive cell line among the cell lines screened) via the activation of caspase 3, up-regulation of bax, and down-regulation of bcl-2. Furthermore, its inhibitory activity on the level of vascular endothelial growth factor was also verified by ELISA.

  9. Endoplasmic reticulum chaperone glucose regulated protein 170-Pokemon complexes elicit a robust antitumor immune response in vivo.

    Science.gov (United States)

    Yuan, Bangqing; Xian, Ronghua; Wu, Xianqu; Jing, Junjie; Chen, Kangning; Liu, Guojun; Zhou, Zhenhua

    2012-07-01

    Previous evidence suggested that the stress protein grp170 can function as a highly efficient molecular chaperone, binding to large protein substrates and acting as a potent vaccine against specific tumors when purified from the same tumor. In addition, Pokemon can be found in almost all malignant tumor cells and is regarded to be a promising candidate for the treatment of tumors. However, the potential of the grp170-Pokemon chaperone complex has not been well described. In the present study, the natural chaperone complex between grp170 and the Pokemon was formed by heat shock, and its immunogenicity was detected by ELISPOT and (51)Cr-release assays in vitro and by tumor bearing models in vivo. Our results demonstrated that the grp170-Pokemon chaperone complex could elicit T cell responses as determined by ELISPOT and (51)Cr-release assays. In addition, immunized C57BL/6 mice were challenged with subcutaneous (s.c.) injection of Lewis cancer cells to induce primary tumors. Treatment of mice with the grp170-Pokemon chaperone complex also significantly inhibited tumor growth and prolonged the life span of tumor-bearing mice. Our results indicated that the grp170-Pokemon chaperone complex might represent a powerful approach to tumor immunotherapy and have significant potential for clinical application. Copyright © 2012 Elsevier GmbH. All rights reserved.

  10. Intratumoral interleukin-21 increases antitumor immunity, tumor-infiltrating CD8+ T-cell density and activity, and enlarges draining lymph nodes

    DEFF Research Database (Denmark)

    Søndergaard, Henrik; Galsgaard, Elisabeth D; Bartholomaeussen, Monica

    2010-01-01

    Interleukin (IL)-21 is a novel cytokine in clinical development for the treatment of cancer. In this study, we have compared the efficacy of subcutaneous and intratumoral (IT) administration of IL-21 protein in two syngeneic mouse tumor models, RenCa renal cell carcinoma and B16 melanoma......, and investigated the mechanisms by which IL-21 enhances CD8 T-cell-mediated antitumor immunity. We found that in comparison to subcutaneous administration, IT administration of IL-21 more potently inhibited tumor growth and increased survival. This correlated with increased densities of tumor-infiltrating CD8...... and CD4CD25 T cells, but not CD4CD25FoxP3 T cells. Furthermore, IT administration of IL-21 increased degranulation, and expression of interferon-gamma and granzyme B in tumor-infiltrating CD8 T cells. Tumors injected with IL-21 grew slower than contralateral tumors, suggesting that the increased efficacy...

  11. Intratumoral Interleukin-21 Increases Antitumor Immunity, Tumor-infiltrating CD8(+) T-cell Density and Activity, and Enlarges Draining Lymph Nodes

    DEFF Research Database (Denmark)

    Sondergaard, H.; Galsgaard, E.D.; Bartholomaeussen, M.

    2010-01-01

    Interleukin (IL)-21 is a novel cytokine in clinical development for the treatment of cancer. In this study, we have compared the efficacy of subcutaneous and intratumoral (IT) administration of IL-21 protein in two syngeneic mouse tumor models, RenCa renal cell carcinoma and B16 melanoma......, and investigated the mechanisms by which IL-21 enhances CD8(+) T-cell-mediated antitumor immunity. We found that in comparison to subcutaneous administration, IT administration of IL-21 more potently inhibited tumor growth and increased survival. This correlated with increased densities of tumor-infiltrating CD8......(+) and CD4(+) CD25(-) T cells, but not CD4(+) CD25(+) FoxP3(+) T cells. Furthermore, IT administration of IL-21 increased degranulation, and expression of interferon-gamma and granzyme B in tumor-infiltrating CD8(+) T cells. Tumors injected with IL-21 grew slower than contralateral tumors, suggesting...

  12. Reversibility of alcohol-induced immune depression

    DEFF Research Database (Denmark)

    Tønnesen, H; Kaiser, A H; Nielsen, B B

    1992-01-01

    Alcohol abusers have suppressed cellular immune function. The aim of the study was to investigate the time of sobriety required to normalize immune function. Delayed hypersensitivity was investigated during disulfiram controlled abstinence in ten heavy alcoholics and in seven moderate drinkers wi...

  13. Therapeutic administration of IL-15 superagonist complex ALT-803 leads to long-term survival and durable antitumor immune response in a murine glioblastoma model.

    Science.gov (United States)

    Mathios, Dimitrios; Park, Chul-Kee; Marcus, Warren D; Alter, Sarah; Rhode, Peter R; Jeng, Emily K; Wong, Hing C; Pardoll, Drew M; Lim, Michael

    2016-01-01

    Glioblastoma is the most aggressive primary central nervous system malignancy with a poor prognosis in patients. Despite the need for better treatments against glioblastoma, very little progress has been made in discovering new therapies that exhibit superior survival benefit than the standard of care. Immunotherapy has been shown to be a promising treatment modality that could help improve clinical outcomes of glioblastoma patients by assisting the immune system to overcome the immunosuppressive tumor environment. Interleukin-15 (IL-15), a cytokine shown to activate several effector components of the immune system, may serve as an excellent immunotherapeutic candidate for the treatment of glioblastoma. Thus, we evaluated the efficacy of an IL-15 superagonist complex (IL-15N72D:IL-15RαSu-Fc; also known as ALT-803) in a murine GL261-luc glioblastoma model. We show that ALT-803, as a single treatment as well as in combination with anti-PD-1 antibody or stereotactic radiosurgery, exhibits a robust antitumor immune response resulting in a prolonged survival including complete remission in tumor bearing mice. In addition, ALT-803 treatment results in long-term immune memory against glioblastoma tumor rechallenge. Flow cytometric analysis of tumor infiltrating immune cells shows that ALT-803 leads to increased percentage of CD8+-cell infiltration, but not the NK cells, and IFN-γ production into the tumor microenvironment. Cell depletion studies, in accordance with the flow cytometric results, show that the ALT-803 therapeutic effect is dependent on CD4+ and CD8+ cells. These results provide a rationale for evaluating the therapeutic activity of ALT-803 against glioblastoma in the clinical setting. © 2015 UICC.

  14. Homeostatic T Cell Expansion to Induce Anti-Tumor Antoimmunity in Breast Cancer

    Science.gov (United States)

    2005-04-01

    response by manipulating the composition of the infused T cells; and (c) to potentiate the anti-tumor effect by using T cell survival and proliferation... antineoplastic drugs with tumor vaccines. Cancer Immunol Immunother 52:680 79. Theofilopoulos AN, Dummer W, Kono DH (2001) T cell homeostasis and systemic...recovered were approved by the Institutional Animal Care Committee. 7 days after transfer had undergone one to four cell divisions, with Donor cells no

  15. Engagement of immune effector cells by trastuzumab induces HER2/ERBB2 downregulation in cancer cells through STAT1 activation

    Science.gov (United States)

    2014-01-01

    Introduction Trastuzumab has been widely used for the treatment of human epidermal growth factor receptor 2 (HER2) overexpressing breast cancer for more than a decade. However, reports on the involvement of HER2 downregulation in trastuzumab’s mechanism of action are inconsistent. The aim of this study is to investigate if the dependence of trastuzumab-mediated cancer cell HER2 downregulation on immune effector cells represents a novel mechanism of action for trastuzumab. Methods HER2 expression was evaluated by Western blotting, flow cytometry, and real-time polymerase chain reaction (PCR) in cell lysates from co-cultures of multiple cancer cell lines with peripheral blood mononuclear cells (PBMCs) in the presence or absence of trastuzumab. The engagement of immune cells by trastuzumab through Fc gamma receptors (FcγRs) was tested using three trastuzumab variants with compromised or no Fc (fragment crystallizable) functions and FcγRs blocking experiments. The engagement of immune cells by trastuzumab in HER2 downregulation was also evaluated in in vivo mouse xenograft tumor models. Results HER2 downregulation of cancer cells by trastuzumab occurred only when trastuzumab was actively engaged with immune cells and cancer cells, as demonstrated consistently in co-cultures of cancer cell lines with PBMCs and in vivo mouse xenograft tumor models. We further demonstrated that HER2 downregulation in cancer cells by immune-cell-engaged trastuzumab was at the transcriptional level, not through the HER2 degradation pathway. Activation of signal transducer and activator of transcription 1 (STAT1) in cancer cells by the increased interferon gamma (IFN-γ) production in immune cells played an important role in downregulating HER2 in cancer cells upon engagement of immune cells by trastuzumab. Furthermore, HER2 downregulation in cancer cells induced by trastuzumab engagement of immune cells was correlated with the antibody’s antitumor efficacy in vivo. Conclusions This

  16. Ubiquitin-specific Protease-7 Inhibition Impairs Tip60-dependent Foxp3+ T-regulatory Cell Function and Promotes Antitumor Immunity

    Directory of Open Access Journals (Sweden)

    Liqing Wang

    2016-11-01

    Full Text Available Foxp3+ T-regulatory (Treg cells are known to suppress protective host immune responses to a wide variety of solid tumors, but their therapeutic targeting is largely restricted to their transient depletion or “secondary” modulation, e.g. using anti-CTLA-4 monoclonal antibody. Our ongoing studies of the post-translational modifications that regulate Foxp3 demonstrated that the histone/protein acetyltransferase, Tip60, plays a dominant role in promoting acetylation, dimerization and function in Treg cells. We now show that the ubiquitin-specific protease, Usp7, controls Treg function largely by stabilizing the expression and promoting the multimerization of Tip60 and Foxp3. Genetic or pharmacologic targeting of Usp7 impairs Foxp3+ Treg suppressive functions, while conventional T cell responses remain intact. As a result, pharmacologic inhibitors of Usp7 can limit tumor growth in immunocompetent mice, and promote the efficacy of antitumor vaccines and immune checkpoint therapy with anti-PD1 monoclonal antibody in murine models. Hence, pharmacologic therapy with Usp7 inhibitors may have an important role in future cancer immunotherapy.

  17. Dysregulation of TGFβ1 Activity in Cancer and Its Influence on the Quality of Anti-Tumor Immunity

    Directory of Open Access Journals (Sweden)

    Kristian M. Hargadon

    2016-08-01

    Full Text Available TGFβ1 is a pleiotropic cytokine that exhibits a variety of physiologic and immune regulatory functions. Although its influence on multiple cell types is critical for the regulation of numerous biologic processes in the host, dysregulation of both TGFβ1 expression and activity is frequently observed in cancer and contributes to various aspects of cancer progression. This review focuses on TGFβ1’s contribution to tumor immune suppression and escape, with emphasis on the influence of this regulatory cytokine on the differentiation and function of dendritic cells and T cells. Clinical trials targeting TGFβ1 in cancer patients are also reviewed, and strategies for future therapeutic interventions that build on our current understanding of immune regulation by TGFβ1 are discussed.

  18. Dysregulation of TGFβ1 Activity in Cancer and Its Influence on the Quality of Anti-Tumor Immunity.

    Science.gov (United States)

    Hargadon, Kristian M

    2016-08-31

    TGFβ1 is a pleiotropic cytokine that exhibits a variety of physiologic and immune regulatory functions. Although its influence on multiple cell types is critical for the regulation of numerous biologic processes in the host, dysregulation of both TGFβ1 expression and activity is frequently observed in cancer and contributes to various aspects of cancer progression. This review focuses on TGFβ1's contribution to tumor immune suppression and escape, with emphasis on the influence of this regulatory cytokine on the differentiation and function of dendritic cells and T cells. Clinical trials targeting TGFβ1 in cancer patients are also reviewed, and strategies for future therapeutic interventions that build on our current understanding of immune regulation by TGFβ1 are discussed.

  19. Bryostatin 1 induces differentiation and potentiates the antitumor effect of Auristatin PE in a human pancreatic tumor (PANC-1) xenograft model.

    Science.gov (United States)

    Mohammad, R M; Adsay, N V; Philip, P A; Pettit, G R; Vaitkevicius, V K; Sarkar, F H

    2001-10-01

    Pancreatic cancer has the worst prognosis of all cancers with a dismal 5-year survival rate. Hence, there is a tremendous need for development of new and effective therapy for this tumor. In an earlier study we reported a potent antitumor activity of Auristatin PE (AuriPE) against pancreatic tumor. In addition, we have also reported that bryostatin 1 (bryo1) induces differentiation of leukemia cells, but the effect of bryo1 has not been investigated in pancreatic tumors. This is the first report where we demonstrate that bryo1 induces differentiation and potentiates the antitumor effect of AuriPE in a human pancreatic tumor (PANC-1) xenograft model. A xenograft model was established by injecting the PANC-1 cells s.c. in severe combined immune deficient (SCID) mice. After development of the s.c. tumors, tumors were dissected and small fragments were transplanted in vivo to new SCID mice, with a success rate of 100% and a doubling time of 4.8 days. The SCID mouse xenograft model was used to test the in vivo differentiation effect of bryo1 and its efficacy when given alone or in combination with AuriPE. Sections from paraffin-embedded tumors excised from untreated (control) SCID mice revealed typical poorly differentiated adenocarcinoma of the pancreas. Interestingly, sections of s.c. tumors taken from bryo1-treated mice revealed carcinomas that were much lower grade and less aggressive, and displayed prominent squamous and glandular differentiation. In this study, the tumor growth inhibition (T/C), activity score and cure rate for bryo1, AuriPE and bryo1+AuriPE were 80%, (+) and 0/4; 0.0%, (++++) and 3/5; and 0.0%, (++++) and 3/4, respectively. Mice treated with either AuriPE or bryo1+AuriPE were free of tumors for more than 150 days and were considered cured. The use of bryo1 as a novel differentiating agent and its combination with AuriPE should be further explored for the treatment of adenocarcinoma of the pancreas.

  20. Delivery of human NKG2D-IL-15 fusion gene by chitosan nanoparticles to enhance antitumor immunity

    Energy Technology Data Exchange (ETDEWEB)

    Yan, Chen; Jie, Leng; Yongqi, Wang [Department of Immunology, School of Medicine, Yangzhou University, Yangzhou, 225009 (China); Weiming, Xiao [Department of Gastroenterology, The Second Clinical Medical College, Yangzhou University, Yangzhou, 225009 (China); Juqun, Xi [Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou, 225009 (China); Yanbing, Ding [Department of Gastroenterology, The Second Clinical Medical College, Yangzhou University, Yangzhou, 225009 (China); Li, Qian [Department of Immunology, School of Medicine, Yangzhou University, Yangzhou, 225009 (China); Xingyuan, Pan [Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou, 225009 (China); Mingchun, Ji [Department of Immunology, School of Medicine, Yangzhou University, Yangzhou, 225009 (China); Weijuan, Gong, E-mail: wjgong@yzu.edu.cn [Department of Immunology, School of Medicine, Yangzhou University, Yangzhou, 225009 (China); Department of Gastroenterology, The Second Clinical Medical College, Yangzhou University, Yangzhou, 225009 (China); Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou, 225009 (China); Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou, 225009 (China); Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009 (China)

    2015-07-31

    Nanoparticles are becoming promising carriers for gene delivery because of their high capacity in gene loading and low cell cytotoxicity. In this study, a chitosan-based nanoparticle encapsulated within a recombinant pcDNA3.1-dsNKG2D-IL-15 plasmid was generated. The fused dsNKG2D-IL-15 gene fragment consisted of double extracellular domains of NKG2D with IL-15 gene at downstream. The average diameter of the gene nanoparticles ranged from 200 nm to 400 nm, with mean zeta potential value of 53.8 ± 6.56 mV. The nanoparticles which were loaded with the dsNKG2D-IL-15 gene were uptaken by tumor cells with low cytotoxicity. Tumor cells pre-transfected by gene nanopartilces stimulated NK and T cells in vitro. Intramuscular injection of gene nanoparticles suppressed tumor growth and prolonged survival of tumor-bearing mice through activation of NK and CD8{sup +} T cells. Thus, chitosan-based nanoparticle delivery of dsNKG2D-IL-15 gene vaccine can be potentially used for tumor therapy. - Highlights: • Generation of a nanoparticle for delivery of dsNKG2D-IL-15 gene. • Characterization of the gene nanoparticle. • Antitumor activity mediated by the gene nanoparticle.

  1. Intratumoral Injection of an Adenovirus Expressing Interleukin 2 Induces Regression and Immunity in a Murine Breast Cancer Model

    Science.gov (United States)

    Addison, Christina L.; Braciak, Todd; Ralston, Robert; Muller, William J.; Gauldie, Jack; Graham, Frank L.

    1995-08-01

    Rodent tumor cells engineered to secrete cytokines such as interleukin 2 (IL-2) or IL-4 are rejected by syngeneic recipients due to an enhanced antitumor host immune response. An adenovirus vector (AdCAIL-2) containing the human IL-2 gene has been constructed and shown to direct secretion of high levels of human IL-2 in infected tumor cells. AdCAIL-2 induces regression of tumors in a transgenic mouse model of mammary adenocarcinoma following intratumoral injection. Elimination of existing tumors in this way results in immunity against a second challenge with tumor cells. These findings suggest that adenovirus vectors expressing cytokines may form the basis for highly effective immunotherapies of human cancers.

  2. Mechanisms underlying UV-induced immune suppression

    Energy Technology Data Exchange (ETDEWEB)

    Ullrich, Stephen E. [Department of Immunology, University of Texas, MD Anderson Cancer Center, South Campus Research Building 1, 7455 Fannin St., P.O. Box 301402, Houston, TX 77030-1903 (United States)]. E-mail: sullrich@mdanderson.org

    2005-04-01

    Skin cancer is the most prevalent form of human neoplasia. Estimates suggest that in excess of one million new cases of skin cancer will be diagnosed this year alone in the United States (www.cancer.org/statistics). Fortunately, because of their highly visible location, skin cancers are more rapidly diagnosed and more easily treated than other types of cancer. Be that as it may, approximately 10,000 Americans a year die from skin cancer. The cost of treating non-melanoma skin cancer is estimated to be in excess of US$ 650 million a year [J.G. Chen, A.B. Fleischer, E.D. Smith, C. Kancler, N.D. Goldman, P.M. Williford, S.R. Feldman, Cost of non-melanoma skin cancer treatment in the United States, Dermatol. Surg. 27 (2001) 1035-1038], and when melanoma is included, the estimated cost of treating skin cancer in the United States is estimated to rise to US$ 2.9 billion annually (www.cancer.org/statistics). Because the morbidity and mortality associated with skin cancer is a major public health problem, it is important to understand the mechanisms underlying skin cancer development. The primary cause of skin cancer is the ultraviolet (UV) radiation found in sunlight. In addition to its carcinogenic potential, UV radiation is also immune suppressive. In fact, data from studies with both experimental animals and biopsy proven skin cancer patients suggest that there is an association between the immune suppressive effects of UV radiation and its carcinogenic potential. The focus of this manuscript will be to review the mechanisms underlying the induction of immune suppression following UV exposure. Particular attention will be directed to the role of soluble mediators in activating immune suppression.

  3. Mechanisms underlying UV-induced immune suppression

    International Nuclear Information System (INIS)

    Ullrich, Stephen E.

    2005-01-01

    Skin cancer is the most prevalent form of human neoplasia. Estimates suggest that in excess of one million new cases of skin cancer will be diagnosed this year alone in the United States (www.cancer.org/statistics). Fortunately, because of their highly visible location, skin cancers are more rapidly diagnosed and more easily treated than other types of cancer. Be that as it may, approximately 10,000 Americans a year die from skin cancer. The cost of treating non-melanoma skin cancer is estimated to be in excess of US$ 650 million a year [J.G. Chen, A.B. Fleischer, E.D. Smith, C. Kancler, N.D. Goldman, P.M. Williford, S.R. Feldman, Cost of non-melanoma skin cancer treatment in the United States, Dermatol. Surg. 27 (2001) 1035-1038], and when melanoma is included, the estimated cost of treating skin cancer in the United States is estimated to rise to US$ 2.9 billion annually (www.cancer.org/statistics). Because the morbidity and mortality associated with skin cancer is a major public health problem, it is important to understand the mechanisms underlying skin cancer development. The primary cause of skin cancer is the ultraviolet (UV) radiation found in sunlight. In addition to its carcinogenic potential, UV radiation is also immune suppressive. In fact, data from studies with both experimental animals and biopsy proven skin cancer patients suggest that there is an association between the immune suppressive effects of UV radiation and its carcinogenic potential. The focus of this manuscript will be to review the mechanisms underlying the induction of immune suppression following UV exposure. Particular attention will be directed to the role of soluble mediators in activating immune suppression

  4. Cell-Centric View of Apoptosis and Apoptotic Cell Death-Inducing Antitumoral Strategies

    Directory of Open Access Journals (Sweden)

    Maria Dolores Boyano

    2011-03-01

    Full Text Available Programmed cell death and especially apoptotic cell death, occurs under physiological conditions and is also desirable under pathological circumstances. However, the more we learn about cellular signaling cascades, the less plausible it becomes to find restricted and well-limited signaling pathways. In this context, an extensive description of pathway-connections is necessary in order to point out the main regulatory molecules as well as to select the most appropriate therapeutic targets. On the other hand, irregularities in programmed cell death pathways often lead to tumor development and cancer-related mortality is projected to continue increasing despite the effort to develop more active and selective antitumoral compounds. In fact, tumor cell plasticity represents a major challenge in chemotherapy and improvement on anticancer therapies seems to rely on appropriate drug combinations. An overview of the current status regarding apoptotic pathways as well as available chemotherapeutic compounds provides a new perspective of possible future anticancer strategies.

  5. Oroxylin A induced apoptosis of human hepatocellular carcinoma cell line HepG2 was involved in its antitumor activity

    International Nuclear Information System (INIS)

    Hu Yang; Yang Yong; You Qidong; Liu Wei; Gu Hongyan; Zhao Li; Zhang Kun; Wang Wei; Wang Xiaotang; Guo Qinglong

    2006-01-01

    We previously reported that wogonin, a flavonoid compound, was a potent apoptosis inducer of human hepatoma SMMC-7721 cells and murine sarcoma S180 cells. In the present study, the effect of oroxylin A, one wogonin structurally related flavonoid isolated from Scutellariae radix, on human hepatocellular carcinoma cell line HepG2 was examined and molecular mechanisms were also investigated. Oroxylin A inhibited HepG2 cell proliferation in a concentration- and time-dependent manner measured by MTT-assay. Treatment with an apoptosis-inducing concentration of oroxylin A caused typical morphological changes and apoptotic blebbing in HepG2 cells. DNA fragmentation assay was used to examine later apoptosis induced by oroxylin A. FACScan analysis revealed a dramatic increase in the number of apoptotic and G 2 /M phase arrest cells after oroxylin A treatment. The pro-apoptotic activity of oroxylin A was attributed to its ability to modulate the concerted expression of Bcl-2, Bax, and pro-caspase-3 proteins. The expression of Bcl-2 protein and pro-caspase-3 protein was dramatically decreased after treatment with oroxylin A. These results demonstrated that oroxylin A could effectively induce programmed cell death and suggested that it could be a promising antitumor drug

  6. The role of epidermal cytokines in the generation of cutaneous immune reactions and ultraviolet radiation-induced immune suppression

    International Nuclear Information System (INIS)

    Ullrich, S.E.

    1995-01-01

    The immune suppression generated by UV exposure is a major risk factor for skin cancer patients. This finding has fuelled efforts to understand the mechanisms involved in the immune suppression induced by exposure to UV radiation. This article reviews the recent findings on the role of epidermal cytokines in the generation of an immune response and their role in the induction of immune suppression induced by UV exposure. (UK)

  7. Maternal immunity enhances Mycoplasma hyopneumoniae vaccination induced cell-mediated immune responses in piglets.

    Science.gov (United States)

    Bandrick, Meggan; Theis, Kara; Molitor, Thomas W

    2014-06-05

    Passively acquired maternal derived immunity (MDI) is a double-edged sword. Maternal derived antibody-mediated immunity (AMI) and cell-mediated immunity (CMI) are critical immediate defenses for the neonate; however, MDI may interfere with the induction of active immunity in the neonate, i.e. passive interference. The effect of antigen-specific MDI on vaccine-induced AMI and CMI responses to Mycoplasma hyopneumoniae (M. hyopneumoniae) was assessed in neonatal piglets. To determine whether CMI and AMI responses could be induced in piglets with MDI, piglets with high and low levels of maternal M. hyopneumoniae-specific immunity were vaccinated against M. hyopneumoniae at 7 d of age. Piglet M. hyopneumoniae-specific antibody, lymphoproliferation, and delayed type hypersensitivity (DTH) responses were measured 7 d and 14 d post vaccination. Piglets with M. hyopneumoniae-specific MDI failed to show vaccine-induced AMI responses; there was no rise in M. hyopneumoniae antibody levels following vaccination of piglets in the presence of M. hyopneumoniae-specific MDI. However, piglets with M. hyopneumoniae-specific MDI had primary (antigen-specific lymphoproliferation) and secondary (DTH) M. hyopneumoniae-specific CMI responses following vaccination. In this study neonatal M. hyopneumoniae-specific CMI was not subject to passive interference by MDI. Further, it appears that both maternal derived and endogenous CMI contribute to M. hyopneumoniae-specific CMI responses in piglets vaccinated in the face of MDI.

  8. Immune markers and correlates of protection for vaccine induced immune responses

    DEFF Research Database (Denmark)

    Thakur, Aneesh; Pedersen, Lasse Eggers; Jungersen, Gregers

    2012-01-01

    , through recombinant major histocompatibility complex (MHC) class I tetramers loaded with relevant peptides, has opened a new vista to include CTL responses in the evaluation of protective immune responses. Here, we review different immune markers and new candidates for correlates of a protective vaccine......Vaccines have been a major innovation in the history of mankind and still have the potential to address the challenges posed by chronic intracellular infections including tuberculosis, HIV and malaria which are leading causes of high morbidity and mortality across the world. Markers...... of an appropriate humoral response currently remain the best validated correlates of protective immunity after vaccination. Despite advancements in the field of immunology over the past few decades currently there are, however, no sufficiently validated immune correlates of vaccine induced protection against...

  9. Immunometabolic Pathways in BCG-Induced Trained Immunity.

    Science.gov (United States)

    Arts, Rob J W; Carvalho, Agostinho; La Rocca, Claudia; Palma, Carla; Rodrigues, Fernando; Silvestre, Ricardo; Kleinnijenhuis, Johanneke; Lachmandas, Ekta; Gonçalves, Luís G; Belinha, Ana; Cunha, Cristina; Oosting, Marije; Joosten, Leo A B; Matarese, Giuseppe; van Crevel, Reinout; Netea, Mihai G

    2016-12-06

    The protective effects of the tuberculosis vaccine Bacillus Calmette-Guerin (BCG) on unrelated infections are thought to be mediated by long-term metabolic changes and chromatin remodeling through histone modifications in innate immune cells such as monocytes, a process termed trained immunity. Here, we show that BCG induction of trained immunity in monocytes is accompanied by a strong increase in glycolysis and, to a lesser extent, glutamine metabolism, both in an in-vitro model and after vaccination of mice and humans. Pharmacological and genetic modulation of rate-limiting glycolysis enzymes inhibits trained immunity, changes that are reflected by the effects on the histone marks (H3K4me3 and H3K9me3) underlying BCG-induced trained immunity. These data demonstrate that a shift of the glucose metabolism toward glycolysis is crucial for the induction of the histone modifications and functional changes underlying BCG-induced trained immunity. The identification of these pathways may be a first step toward vaccines that combine immunological and metabolic stimulation. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  10. Cellular immunotherapy using irradiated lung cancer cell vaccine co-expressing GM-CSF and IL-18 can induce significant antitumor effects

    International Nuclear Information System (INIS)

    Tian, Hongwei; Zhang, Xiaomei; Dai, Lei; Chen, Xiaolei; Zhang, Shuang; Yang, Yang; Yu, Dechao; Wei, Yuquan; Deng, Hongxin; Shi, Gang; Yang, Guoyou; Zhang, Junfeng; Li, Yiming; Du, Tao; Wang, Jianzhou; Xu, Fen; Cheng, Lin

    2014-01-01

    Although the whole tumor cell vaccine can provide the best source of immunizing antigens, there is still a limitation that most tumors are not naturally immunogenic. Tumor cells genetically modified to secrete immune activating cytokines have been proved to be more immunogenic. IL-18 could augment proliferation of T cells and cytotoxicity of NK cells. GM-CSF could stimulate dendritic cells, macrophages and enhance presentation of tumor antigens. In our study, we used mouse GM-CSF combined with IL-18 to modify Lewis lung cancer LL/2, then investigated whether vaccination could suppress tumor growth and promote survival. The Lewis lung cancer LL/2 was transfected with co-expressing mouse GM-CSF and IL-18 plasmid by cationic liposome, then irradiated with a sublethal dose X ray (100 Gy) to prepare vaccines. Mice were subcutaneously immunized with this inactivated vaccine and then inoculated with autologous LL/2 to estimate the antitumor efficacy. The studies reported here showed that LL/2 tumor cell vaccine modified by a co-expressing mouse GM-CSF and IL-18 plasmid could significantly inhibit tumor growth and increased survival of the mice bearing LL/2 tumor whether prophylactic or adoptive immunotherapy in vivo. A significant reduction of proliferation and increase of apoptosis were also observed in the tumor treated with vaccine of co-expressing GM-CSF and IL-18. The potent antitumor effect correlated with higher secretion levels of pro-inflammatory cytokines such as IL-18, GM-CSF, interferon-γ in serum, the proliferation of CD4 + IFN-γ + , CD8 + IFN-γ + T lymphocytes in spleen and the infiltration of CD4 + , CD8 + T in tumor. Furthermore, the mechanism of tumor-specific immune response was further proved by 51 Cr cytotoxicity assay in vitro and depletion of CD4, CD8, NK immune cell subsets in vivo. The results suggested that the antitumor mechanism was mainly depended on CD4 + , CD8 + T lymphocytes. These results provide a new insight into therapeutic mechanisms

  11. Tumor-Derived Exosomes and Their Role in Tumor-Induced Immune Suppression

    Directory of Open Access Journals (Sweden)

    Theresa L. Whiteside

    2016-10-01

    Full Text Available Tumor-derived exosomes (TEX are emerging as critical components of an intercellular information network between the tumor and the host. The tumor escapes from the host immune system by using a variety of mechanisms designed to impair or eliminate anti-tumor immunity. TEX carrying a cargo of immunoinhibitory molecules and factors represent one such mechanism. TEX, which are present in all body fluids of cancer patients, deliver negative molecular or genetic signals to immune cells re-programming their functions. Although TEX can also stimulate immune activity, in the microenvironments dominated by the tumor, TEX tend to mediate immune suppression thus promoting tumor progression. The TEX content, in part resembling that of the parent cell, may serve as a source of cancer biomarkers. TEX also interfere with immune therapies. A better understanding of TEX and their contribution to cancer progression and cancer patients’ response to immune therapies represents a challenging new field of investigation.

  12. Validating the pivotal role of the immune system in low-dose radiation-induced tumor inhibition in Lewis lung cancer-bearing mice.

    Science.gov (United States)

    Zhou, Lei; Zhang, Xiaoying; Li, Hui; Niu, Chao; Yu, Dehai; Yang, Guozi; Liang, Xinyue; Wen, Xue; Li, Min; Cui, Jiuwei

    2018-04-01

    Although low-dose radiation (LDR) possesses the two distinct functions of inducing hormesis and adaptive responses, which result in immune enhancement and tumor inhibition, its clinical applications have not yet been elucidated. The major obstacle that hinders the application of LDR in the clinical setting is that the mechanisms underlying induction of tumor inhibition are unclear, and the risks associated with LDR are still unknown. Thus, to overcome this obstacle and elucidate the mechanisms mediating the antitumor effects of LDR, in this study, we established an in vivo lung cancer model to investigate the participation of the immune system in LDR-induced tumor inhibition and validated the pivotal role of the immune system by impairing immunity with high-dose radiation (HDR) of 1 Gy. Additionally, the LDR-induced adaptive response of the immune system was also observed by sequential HDR treatment in this mouse model. We found that LDR-activated T cells and natural killer cells and increased the cytotoxicity of splenocytes and the infiltration of T cells in the tumor tissues. In contrast, when immune function was impaired by HDR pretreatment, LDR could not induce tumor inhibition. However, when LDR was administered before HDR, the immunity could be protected from impairment, and tumor growth could be inhibited to some extent, indicating the induction of the immune adaptive response by LDR. Therefore, we demonstrated that immune enhancement played a key role in LDR-induced tumor inhibition. These findings emphasized the importance of the immune response in tumor radiotherapy and may help promote the application of LDR as a novel approach in clinical practice. © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  13. Chimeric Antigen Receptor-Engineered NK-92 Cells: An Off-the-Shelf Cellular Therapeutic for Targeted Elimination of Cancer Cells and Induction of Protective Antitumor Immunity

    Directory of Open Access Journals (Sweden)

    Congcong Zhang

    2017-05-01

    Full Text Available Significant progress has been made in recent years toward realizing the potential of natural killer (NK cells for cancer immunotherapy. NK cells can respond rapidly to transformed and stressed cells and have the intrinsic potential to extravasate and reach their targets in almost all body tissues. In addition to donor-derived primary NK cells, also the established NK cell line NK-92 is being developed for adoptive immunotherapy, and general safety of infusion of irradiated NK-92 cells has been established in phase I clinical trials with clinical responses observed in some of the cancer patients treated. To enhance their therapeutic utility, NK-92 cells have been modified to express chimeric antigen receptors (CARs composed of a tumor-specific single chain fragment variable antibody fragment fused via hinge and transmembrane regions to intracellular signaling moieties such as CD3ζ or composite signaling domains containing a costimulatory protein together with CD3ζ. CAR-mediated activation of NK cells then bypasses inhibitory signals and overcomes NK resistance of tumor cells. In contrast to primary NK cells, CAR-engineered NK-92 cell lines suitable for clinical development can be established from molecularly and functionally well-characterized single cell clones following good manufacturing practice-compliant procedures. In preclinical in vitro and in vivo models, potent antitumor activity of NK-92 variants targeted to differentiation antigens expressed by hematologic malignancies, and overexpressed or mutated self-antigens associated with solid tumors has been found, encouraging further development of CAR-engineered NK-92 cells. Importantly, in syngeneic mouse tumor models, induction of endogenous antitumor immunity after treatment with CAR-expressing NK-92 cells has been demonstrated, resulting in cures and long-lasting immunological memory protecting against tumor rechallenge at distant sites. Here, we summarize the current status and future

  14. Chimeric Antigen Receptor-Engineered NK-92 Cells: An Off-the-Shelf Cellular Therapeutic for Targeted Elimination of Cancer Cells and Induction of Protective Antitumor Immunity.

    Science.gov (United States)

    Zhang, Congcong; Oberoi, Pranav; Oelsner, Sarah; Waldmann, Anja; Lindner, Aline; Tonn, Torsten; Wels, Winfried S

    2017-01-01

    Significant progress has been made in recent years toward realizing the potential of natural killer (NK) cells for cancer immunotherapy. NK cells can respond rapidly to transformed and stressed cells and have the intrinsic potential to extravasate and reach their targets in almost all body tissues. In addition to donor-derived primary NK cells, also the established NK cell line NK-92 is being developed for adoptive immunotherapy, and general safety of infusion of irradiated NK-92 cells has been established in phase I clinical trials with clinical responses observed in some of the cancer patients treated. To enhance their therapeutic utility, NK-92 cells have been modified to express chimeric antigen receptors (CARs) composed of a tumor-specific single chain fragment variable antibody fragment fused via hinge and transmembrane regions to intracellular signaling moieties such as CD3ζ or composite signaling domains containing a costimulatory protein together with CD3ζ. CAR-mediated activation of NK cells then bypasses inhibitory signals and overcomes NK resistance of tumor cells. In contrast to primary NK cells, CAR-engineered NK-92 cell lines suitable for clinical development can be established from molecularly and functionally well-characterized single cell clones following good manufacturing practice-compliant procedures. In preclinical in vitro and in vivo models, potent antitumor activity of NK-92 variants targeted to differentiation antigens expressed by hematologic malignancies, and overexpressed or mutated self-antigens associated with solid tumors has been found, encouraging further development of CAR-engineered NK-92 cells. Importantly, in syngeneic mouse tumor models, induction of endogenous antitumor immunity after treatment with CAR-expressing NK-92 cells has been demonstrated, resulting in cures and long-lasting immunological memory protecting against tumor rechallenge at distant sites. Here, we summarize the current status and future prospects of CAR

  15. Radiation Induced Immune Response in Prostate Cancer

    Science.gov (United States)

    2014-12-01

    dependent cell- mediated phagocytosis ( ADCP ). This research will allow us to characterize antigens and antibodies intended for clinical trials in patients...Moreover, TIP1 is inducible in nearly all mouse models of cancer resulting in opsonization and activation of ADCC and ADCP . Antibodies that we...antibody-dependent cell-mediated phagocytosis ( ADCP ). ScFv antibodies Overall Project Summary Subtask 1.1 Binding of antibodies to irradiated

  16. Radiation-induced augmentation of the immune response

    International Nuclear Information System (INIS)

    Anderson, R.E.; Lefkovits, I.; Troup, G.M.

    1980-01-01

    Radiation-induced augmentation of the immune response has been shown to occur both in vivo and in vitro. Evidence is presented to implicate injury to an extremely radiosensitive T cell in the expression of this phenomenon. Experiments are outlined which could be employed to support or reflect this hypothesis

  17. Cross-serotype immunity induced by immunization with a conserved rhinovirus capsid protein.

    Directory of Open Access Journals (Sweden)

    Nicholas Glanville

    Full Text Available Human rhinovirus (RV infections are the principle cause of common colds and precipitate asthma and COPD exacerbations. There is currently no RV vaccine, largely due to the existence of ∼150 strains. We aimed to define highly conserved areas of the RV proteome and test their usefulness as candidate antigens for a broadly cross-reactive vaccine, using a mouse infection model. Regions of the VP0 (VP4+VP2 capsid protein were identified as having high homology across RVs. Immunization with a recombinant VP0 combined with a Th1 promoting adjuvant induced systemic, antigen specific, cross-serotype, cellular and humoral immune responses. Similar cross-reactive responses were observed in the lungs of immunized mice after infection with heterologous RV strains. Immunization enhanced the generation of heterosubtypic neutralizing antibodies and lung memory T cells, and caused more rapid virus clearance. Conserved domains of the RV capsid therefore induce cross-reactive immune responses and represent candidates for a subunit RV vaccine.

  18. Sonodynamic therapy on chemically induced mammary tumor: pharmacokinetics, tissue distribution and sonodynamically induced antitumor effect of gallium-porphyrin complex ATX-70.

    Science.gov (United States)

    Yumita, Nagahiko; Okuyama, Nobuo; Sasaki, Kazuaki; Umemura, Shin-Ichiro

    2007-11-01

    Sonodynamically induced antitumor effect of a gallium porphyrin complex, ATX-70 was evaluated on a chemically induced mammary tumor in Sprague-Dawley rats. The timing of 24 h after the administration of ATX-70 was chosen for ultrasonic exposure, based on pharmacokinetic analysis of ATX-70 concentrations in the tumor, plasma, skin, and muscle. At an ATX-70 dose not less than 2.5 mg/kg and at a free-field ultrasonic intensity not less than 3 W/cm(2), the synergistic effect between ATX-70 administration and ultrasonic exposure on the tumor growth inhibition was significant. These results suggest that ATX-70 is a potential sonosensitizer for sonodynamic treatment of spontaneous mammary tumors.

  19. Anti-tumor Activity of Toll-Like Receptor 7 Agonists

    Directory of Open Access Journals (Sweden)

    Huju Chi

    2017-05-01

    Full Text Available Toll-like receptors (TLRs are a class of pattern recognition receptors that play a bridging role in innate immunity and adaptive immunity. The activated TLRs not only induce inflammatory responses, but also elicit the development of antigen specific immunity. TLR7, a member of TLR family, is an intracellular receptor expressed on the membrane of endosomes. TLR7 can be triggered not only by ssRNA during viral infections, but also by immune modifiers that share a similar structure to nucleosides. Its powerful immune stimulatory action can be potentially used in the anti-tumor therapy. This article reviewed the anti-tumor activity and mechanism of TLR7 agonists that are frequently applied in preclinical and clinical investigations, and mainly focused on small synthetic molecules, including imiquimod, resiquimod, gardiquimod, and 852A, etc.

  20. Inducible cell death in plant immunity

    DEFF Research Database (Denmark)

    Hofius, Daniel; Tsitsigiannis, Dimitrios I; Jones, Jonathan D G

    2006-01-01

    Programmed cell death (PCD) occurs during vegetative and reproductive plant growth, as typified by autumnal leaf senescence and the terminal differentiation of the endosperm of cereals which provide our major source of food. PCD also occurs in response to environmental stress and pathogen attack......, and these inducible PCD forms are intensively studied due their experimental tractability. In general, evidence exists for plant cell death pathways which have similarities to the apoptotic, autophagic and necrotic forms described in yeast and metazoans. Recent research aiming to understand these pathways...

  1. A Drosophila immune response against Ras-induced overgrowth

    Directory of Open Access Journals (Sweden)

    Thomas Hauling

    2014-03-01

    Full Text Available Our goal is to characterize the innate immune response against the early stage of tumor development. For this, animal models where genetic changes in specific cells and tissues can be performed in a controlled way have become increasingly important, including the fruitfly Drosophila melanogaster. Many tumor mutants in Drosophila affect the germline and, as a consequence, also the immune system itself, making it difficult to ascribe their phenotype to a specific tissue. Only during the past decade, mutations have been induced systematically in somatic cells to study the control of tumorous growth by neighboring cells and by immune cells. Here we show that upon ectopic expression of a dominant-active form of the Ras oncogene (RasV12, both imaginal discs and salivary glands are affected. Particularly, the glands increase in size, express metalloproteinases and display apoptotic markers. This leads to a strong cellular response, which has many hallmarks of the granuloma-like encapsulation reaction, usually mounted by the insect against larger foreign objects. RNA sequencing of the fat body reveals a characteristic humoral immune response. In addition we also identify genes that are specifically induced upon expression of RasV12. As a proof-of-principle, we show that one of the induced genes (santa-maria, which encodes a scavenger receptor, modulates damage to the salivary glands. The list of genes we have identified provides a rich source for further functional characterization. Our hope is that this will lead to a better understanding of the earliest stage of innate immune responses against tumors with implications for mammalian immunity.

  2. [Involvement of cellular immunity and humoral immunity in mixed allergy induced by trichloroethylene].

    Science.gov (United States)

    Xu, Xinyun; Li, Xueyu; Liu, Yuefeng

    2014-12-01

    To investigate whether cellular immunity and humoral immunity are involved in trichlorethylene (TCE)-induced mixed allergy, then provide the scientific basis for the mechanism of this disease. Guinea pigs and rats were tested for this study by application of guinea pig maximization test (GPMT), the animals were randomly divided into negative control, positive control and TCE treatment groups. Animals of these groups were administrated with olive oil, 2, 4-dinitrochlorobenzene (DNCB), and TCE, respectively, by intradermal injection. After TCE administration, rat peripheral blood samples were collected by flow cytometry to detect lymphocytes CD3⁺, CD4⁺, CD8⁺. Guinea pig peripheral blood samples were collected to detect the levels of IgG, IgA, IgM, C3, C4, and the spleens were taken out from guinea pigs after various treatment, mRNA expression of GATA3, T-bet, CTLA4 and Foxp3 in lymphocytes of guinea pig spleen was detected by real-time fluorescent PCR assay. Additionally, TCE allergic dermatitis patients were selected for the study, the peripheral blood samples were collected from the TCE patients group and control group, quantitative PCR was applied to detect mRNA expression of immune-related genes Foxp3, GATA3, CTLA4, T-bet. TCE induced obvious skin allergic reaction in guinea pigs, the sensitization rate was 83.3%, IgG levels in TCE group and positive control increased significantly. Additionally, mRNA expression levels of GATA3, T-bet, CTLA4 significantly elevated in TCE group and positive control, but Foxp3 mRNA levels decreased. The lymphocytes CD3⁺ ratio in TCE group and positive control of rats was higher than that in negative control, we found that there was no statistical difference of CD4⁺, CD8⁺, CD4⁺/CD8⁺ between TCE group and negative control of rats. The mRNA expression levels of Foxp3, GATA3, CTLA4 in TCE patients increased by 115%, 97%, 241%, respectively as compared with the control, T-bet levels decreased by 47%when compared with the

  3. The antitumor natural compound falcarindiol promotes cancer cell death by inducing endoplasmic reticulum stress.

    Science.gov (United States)

    Jin, H R; Zhao, J; Zhang, Z; Liao, Y; Wang, C-Z; Huang, W-H; Li, S-P; He, T-C; Yuan, C-S; Du, W

    2012-08-23

    Falcarindiol (FAD) is a natural polyyne with various beneficial biological activities. We show here that FAD preferentially kills colon cancer cells but not normal colon epithelial cells. Furthermore, FAD inhibits tumor growth in a xenograft tumor model and exhibits strong synergistic killing of cancer cells with 5-fluorouracil, an approved cancer chemotherapeutic drug. We demonstrate that FAD-induced cell death is mediated by induction of endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR). Decreasing the level of ER stress, either by overexpressing the ER chaperone protein glucose-regulated protein 78 (GRP78) or by knockout of components of the UPR pathway, reduces FAD-induced apoptosis. In contrast, increasing the level of ER stress by knocking down GRP78 potentiates FAD-induced apoptosis. Finally, FAD-induced ER stress and apoptosis is correlated with the accumulation of ubiquitinated proteins, suggesting that FAD functions at least in part by interfering with proteasome function, leading to the accumulation of unfolded protein and induction of ER stress. Consistent with this, inhibition of protein synthesis by cycloheximide significantly decreases the accumulation of ubiquitinated proteins and blocks FAD-induced ER stress and cell death. Taken together, our study shows that FAD is a potential new anticancer agent that exerts its activity through inducing ER stress and apoptosis.

  4. TREX1 dictates the immune fate of irradiated cancer cells.

    Science.gov (United States)

    Vanpouille-Box, Claire; Formenti, Silvia C; Demaria, Sandra

    2017-01-01

    The optimal radiation dose and fractionation to induce anti-tumor immunity remain elusive. We recently found that the exonuclease TREX1 abrogates the immunogenicity of irradiated cancer cells by degrading interferon-stimulatory cytosolic dsDNA. TREX1 upregulation by radiation dose per fraction beyond a threshold of 10-12 Gy results in poor synergy with immune checkpoint blockers.

  5. Skin immunization by microneedle patch overcomes statin-induced suppression of immune responses to influenza vaccine.

    Science.gov (United States)

    Vassilieva, Elena V; Wang, Shelly; Li, Song; Prausnitz, Mark R; Compans, Richard W

    2017-12-19

    Recent studies indicated that in elderly individuals, statin therapy is associated with a reduced response to influenza vaccination. The present study was designed to determine effects on the immune response to influenza vaccination induced by statin administration in a mouse model, and investigate potential approaches to improve the outcome of vaccination on the background of statin therapy. We fed middle aged BALB/c mice a high fat "western" diet (WD) alone or supplemented with atorvastatin (AT) for 14 weeks, and control mice were fed with the regular rodent diet. Mice were immunized with a single dose of subunit A/Brisbane/59/07 (H1N1) vaccine, either systemically or with dissolving microneedle patches (MNPs). We observed that a greater age-dependent decline in the hemagglutinin inhibition titers occurred in systemically-immunized mice than in MNP- immunized mice. AT dampened the antibody response in the animals vaccinated by either route of vaccine delivery. However, the MNP-vaccinated AT-treated animals had ~20 times higher total antibody levels to the influenza vaccine than the systemically vaccinated group one month postvaccination. We propose that microneedle vaccination against influenza provides an approach to ameliorate the immunosuppressive effect of statin therapy observed with systemic immunization.

  6. Immunization with avian metapneumovirus harboring chicken Fc induces higher immune responses.

    Science.gov (United States)

    Paudel, Sarita; Easwaran, Maheswaran; Jang, Hyun; Jung, Ho-Kyoung; Kim, Joo-Hun; Shin, Hyun-Jin

    2016-07-15

    In this study, we evaluated the immune responses of avian metapneumovirus harboring chicken Fc molecule. Stable Vero cells expressing chicken Fc chimera on its surface (Vero-cFc) were established, and we confirmed that aMPV grown in Vero-cFc incorporated host derived chimera Fc into the aMPV virions. Immunization of chicken with aMPV-cFc induced higher level of antibodies and inflammatory cytokines; (Interferon (IFN)-γ and Interleukin (IL)-1β) compared to those of aMPV. The increased levels of antibodies and inflammatory cytokines in chicken immunized with aMPV-cFc were statistically significantly (p<0.05) to that of aMPV and control. The aMPV-cFc group also generated the highest neutralizing antibody response. After challenges, chickens immunized with aMPV-cFc showed much less pathological signs in nasal turbinates and trachea so that we could confirm aMPV-cFc induced higher protection than that of aMPV. The greater ability of aMPV harboring chicken Fc to that of aMPV presented it as a possible vaccine candidate. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. Programmed Death Ligand 2 in Cancer-Induced Immune Suppression

    Directory of Open Access Journals (Sweden)

    Esdy N. Rozali

    2012-01-01

    Full Text Available Inhibitory molecules of the B7/CD28 family play a key role in the induction of immune tolerance in the tumor microenvironment. The programmed death-1 receptor (PD-1, with its ligands PD-L1 and PD-L2, constitutes an important member of these inhibitory pathways. The relevance of the PD-1/PD-L1 pathway in cancer has been extensively studied and therapeutic approaches targeting PD-1 and PD-L1 have been developed and are undergoing human clinical testing. However, PD-L2 has not received as much attention and its role in modulating tumor immunity is less clear. Here, we review the literature on the immunobiology of PD-L2, particularly on its possible roles in cancer-induced immune suppression and we discuss the results of recent studies targeting PD-L2 in cancer.

  8. Temperature effects on vaccine induced immunity to viruses in fish

    DEFF Research Database (Denmark)

    Lorenzen, Niels; Lorenzen, Ellen; Rasmussen, Jesper Skou

    a problem in terms of inducing a protective immune response by vaccination in aquaculture, since it is often desirable to vaccinate fish during autumn, winter, or spring. In experimental vaccination trials with rainbow trout (Oncorhynchus mykiss) using a DNA-vaccine encoding the viral glycoprotein of viral...... haemorrhagic septicaemia virus (VHSV), non-specific as well as specific immune mechanisms seemed to be delayed at low temperature. At five weeks post vaccination fish kept at 5C had no detectable response of neutralising antibodies while two thirds of the fish kept at 15C had sero-converted. While protective...... immunity was still established at both temperatures, specificity analysis suggested that protection at the lower temperature was mainly due to non-specific innate antiviral mechanisms, which appeared to last longer at low temperature. This was presumably related to a prolonged persistence of the vaccine...

  9. Candida albicans infection of Caenorhabditis elegans induces antifungal immune defenses.

    Directory of Open Access Journals (Sweden)

    Read Pukkila-Worley

    2011-06-01

    Full Text Available Candida albicans yeast cells are found in the intestine of most humans, yet this opportunist can invade host tissues and cause life-threatening infections in susceptible individuals. To better understand the host factors that underlie susceptibility to candidiasis, we developed a new model to study antifungal innate immunity. We demonstrate that the yeast form of C. albicans establishes an intestinal infection in Caenorhabditis elegans, whereas heat-killed yeast are avirulent. Genome-wide, transcription-profiling analysis of C. elegans infected with C. albicans yeast showed that exposure to C. albicans stimulated a rapid host response involving 313 genes (124 upregulated and 189 downregulated, ~1.6% of the genome many of which encode antimicrobial, secreted or detoxification proteins. Interestingly, the host genes affected by C. albicans exposure overlapped only to a small extent with the distinct transcriptional responses to the pathogenic bacteria Pseudomonas aeruginosa or Staphylococcus aureus, indicating that there is a high degree of immune specificity toward different bacterial species and C. albicans. Furthermore, genes induced by P. aeruginosa and S. aureus were strongly over-represented among the genes downregulated during C. albicans infection, suggesting that in response to fungal pathogens, nematodes selectively repress the transcription of antibacterial immune effectors. A similar phenomenon is well known in the plant immune response, but has not been described previously in metazoans. Finally, 56% of the genes induced by live C. albicans were also upregulated by heat-killed yeast. These data suggest that a large part of the transcriptional response to C. albicans is mediated through "pattern recognition," an ancient immune surveillance mechanism able to detect conserved microbial molecules (so-called pathogen-associated molecular patterns or PAMPs. This study provides new information on the evolution and regulation of the innate

  10. Dendritic-cell-based immunotherapy evokes potent anti-tumor immune responses in CD105+ human renal cancer stem cells.

    Science.gov (United States)

    Zhang, Xiao-Fei; Weng, De-Sheng; Pan, Ke; Zhou, Zi-Qi; Pan, Qiu-Zhong; Zhao, Jing-Jing; Tang, Yan; Jiang, Shan-Shan; Chen, Chang-Long; Li, Yong-Qiang; Zhang, Hong-Xia; Chang, Alfred E; Wicha, Max S; Zeng, Yi-Xin; Li, Qiao; Xia, Jian-Chuan

    2017-11-01

    Cancer stem cells (CSCs) are responsible for tumor initiation, progression, and resistance to therapeutic agents; they are usually less sensitive to conventional cancer therapies, and could cause tumor relapse. An ideal therapeutic strategy would therefore be to selectively target and destroy CSCs, thereby preventing tumor relapse. The aim of the present study was to evaluate the effectiveness of dendritic cells (DCs) pulsed with antigen derived from CD105+ human renal cell carcinoma (RCC) CSCs against renal cancer cells in vitro and in vivo. We identified "stem-like" characteristics of CD105+ cells in two human RCC cell lines: A498 and SK-RC-39. Loading with cell lysates did not change the characteristics of the DCs. However, DCs loaded with lysates derived from CD105+ CSCs induced more functionally specific active T cells and specific antibodies against CSCs, and clearly depressed the tumor growth in mice. Our results could form the basis for a novel strategy to improve the efficacy of DC-based immunotherapy for human RCC. © 2017 Wiley Periodicals, Inc.

  11. Flagella-induced immunity against experimental cholera in adult rabbits.

    Science.gov (United States)

    Yancey, R J; Willis, D L; Berry, L J

    1979-07-01

    The adult rabbit ligated ileal loop model was used to evaluate the prophylactic potential of a crude flagellar (CF) vaccine produced from the classical. Inaba strain CA401. A greater than 1,000-fold increase in the challenge inoculum was required to induce an intestinal fluid response in actively immunized adult rabbits equivalent to that produced in unimmunized animals. Similar protection was afforded against challenge with classical and El Tor biotypes of both Inaba and Ogawa serotypes. Highly virulent 35S-labeled vibrios were inhibited in their ability to associated with the intestinal mucosa of CF-immunized rabbits. The protection conferred by CF immunization was found to be superior to that of a commercial bivalent vaccine and also to that of glutaraldehyde-treated cholera toxoid. The critical immunogenic component of CF appears to be a flagella-derived protein. The immunogenicity of CF was destroyed by heat treatment, and absorption of CF-immune serum with aflagellated mutant vibrios did not diminish its ability to confer a high level of passive protection. The intestinal protection of CF-immunized rabbits was completely reversed by the introduction of both goat anti-rabbit immunoglobulins A and G, but by neither alone.

  12. Salmonella enterica Induces And Subverts The Plant Immune System

    Directory of Open Access Journals (Sweden)

    Ana Victoria Garcia

    2014-04-01

    Full Text Available Infections with Salmonella enterica belong to the most prominent causes of food poisoning and infected fruits and vegetables represent important vectors for salmonellosis. Whereas it was shown that plants raise defense responses against Salmonella, these bacteria persist and proliferate in various plant tissues. Recent reports shed light into the molecular interaction between plants and Salmonella, highlighting the defense pathways induced and the means used by the bacteria to escape the plant immune system and accomplish colonization. It was recently shown that plants detect Salmonella pathogen-associated molecular patterns (PAMPs, such as the flagellin peptide flg22, and activate hallmarks of the defense program known as PAMP-triggered immunity (PTI. Interestingly, certain Salmonella strains carry mutations in the flg22 domain triggering PTI, suggesting that a strategy of Salmonella is to escape plant detection by mutating PAMP motifs. Another strategy may rely on the type III secretion system (T3SS as T3SS mutants were found to induce stronger plant defense responses than wild type bacteria. Although Salmonella effector delivery into plant cells has not been shown, expression of Salmonella effectors in plant tissues shows that these bacteria also possess powerful means to manipulate the plant immune system. Altogether, the data gathered suggest that Salmonella triggers PTI in plants and evolved strategies to avoid or subvert plant immunity.

  13. Salmonella enterica induces and subverts the plant immune system

    KAUST Repository

    García, Ana V.

    2014-04-04

    Infections with Salmonella enterica belong to the most prominent causes of food poisoning and infected fruits and vegetables represent important vectors for salmonellosis. Although it was shown that plants raise defense responses against Salmonella, these bacteria persist and proliferate in various plant tissues. Recent reports shed light into the molecular interaction between plants and Salmonella, highlighting the defense pathways induced and the means used by the bacteria to escape the plant immune system and accomplish colonization. It was recently shown that plants detect Salmonella pathogen-associated molecular patterns (PAMPs), such as the flagellin peptide flg22, and activate hallmarks of the defense program known as PAMP-triggered immunity (PTI). Interestingly, certain Salmonella strains carry mutations in the flg22 domain triggering PTI, suggesting that a strategy of Salmonella is to escape plant detection by mutating PAMP motifs. Another strategy may rely on the type III secretion system (T3SS) as T3SS mutants were found to induce stronger plant defense responses than wild type bacteria. Although Salmonella effector delivery into plant cells has not been shown, expression of Salmonella effectors in plant tissues shows that these bacteria also possess powerful means to manipulate the plant immune system. Altogether, these data suggest that Salmonella triggers PTI in plants and evolved strategies to avoid or subvert plant immunity. 2014 Garca and Hirt.

  14. Endotoxin-induced antitumor activity in the mouse is highly potentiated by muramyl dipeptide

    NARCIS (Netherlands)

    Hofhuis, F.M.A.; Bloksma, N.; Willers, J.M.N.

    1984-01-01

    The ability of aqueous solutions of various endotoxin preparations, muramyl dipeptide (MDP) and combinations of endotoxin and MDP, to induce necrosis and regression of subcutaneous Meth A transplants in mice and their toxicity were studied. While intravenously injected toxic endotoxins, in contrast

  15. Mitochondria Are the Target Organelle of Differentiation-Inducing Factor-3, an Anti-Tumor Agent Isolated from Dictyostelium Discoideum

    Science.gov (United States)

    Kubohara, Yuzuru; Kikuchi, Haruhisa; Matsuo, Yusuke; Oshima, Yoshiteru; Homma, Yoshimi

    2013-01-01

    Differentiation-inducing factor-3 (DIF-3), found in the cellular slime mold Dictyostelium discoideum, and its derivatives such as butoxy-DIF-3 (Bu-DIF-3) are potent anti-tumor agents. However, the precise mechanisms underlying the actions of DIF-3 remain to be elucidated. In this study, we synthesized a green fluorescent derivative of DIF-3, BODIPY-DIF-3, and a control fluorescent compound, Bu-BODIPY (butyl-BODIPY), and investigated how DIF-like molecules behave in human cervical cancer HeLa cells by using both fluorescence and electron microscopy. BODIPY-DIF-3 at 5–20 µ M suppressed cell growth in a dose-dependent manner, whereas Bu-BODIPY had minimal effect on cell growth. When cells were incubated with BODIPY-DIF-3 at 20 µM, it penetrated cell membranes within 0.5 h and localized mainly in mitochondria, while Bu-BODIPY did not stain the cells. Exposure of cells for 1–3 days to DIF-3, Bu-DIF-3, BODIPY-DIF-3, or CCCP (a mitochondrial uncoupler) induced substantial mitochondrial swelling, suppressing cell growth. When added to isolated mitochondria, DIF-3, Bu-DIF-3, and BOIDPY-DIF-3, like CCCP, dose-dependently promoted the rate of oxygen consumption, but Bu-BODIPY did not. Our results suggest that these bioactive DIF-like molecules suppress cell growth, at least in part, by disturbing mitochondrial activity. This is the first report showing the cellular localization and behavior of DIF-like molecules in mammalian tumor cells. PMID:23977224

  16. Inhibition of Hypoxia Inducible Factor Alpha and Astrocyte-Elevated Gene-1 Mediates Cryptotanshinone Exerted Antitumor Activity in Hypoxic PC-3 Cells

    Directory of Open Access Journals (Sweden)

    Hyo-Jeong Lee

    2012-01-01

    Full Text Available Although cryptotanshinone (CT was known to exert antitumor activity in several cancers, its molecular mechanism under hypoxia still remains unclear. Here, the roles of AEG-1 and HIF-1α in CT-induced antitumor activity were investigated in hypoxic PC-3 cells. CT exerted cytotoxicity against prostate cancer cells and suppressed HIF-1α accumulation and AEG-1 expression in hypoxic PC-3 cells. Also, AEG-1 was overexpressed in prostate cancer cells. Interestingly, HIF-1α siRNA transfection enhanced the cleavages of caspase-9,3, and PAPR and decreased expression of Bcl-2 and AEG1 induced by CT in hypoxic PC-3 cells. Of note, DMOG enhanced the stability of AEG-1 and HIF-1α during hypoxia. Additionally, CT significantly reduced cellular level of VEGF in PC-3 cells and disturbed tube formation of HUVECs. Consistently, ChIP assay revealed that CT inhibited the binding of HIF-1α to VEGF promoter. Furthermore, CT at 10 mg/kg suppressed the growth of PC-3 cells in BALB/c athymic nude mice by 46.4% compared to untreated control. Consistently, immunohistochemistry revealed decreased expression of Ki-67, CD34, VEGF, carbonic anhydrase IX, and AEG-1 indices in CT-treated group compared to untreated control. Overall, our findings suggest that CT exerts antitumor activity via inhibition of HIF-1α, AEG1, and VEGF as a potent chemotherapeutic agent.

  17. Immunity booster

    International Nuclear Information System (INIS)

    Stefanescu, Ioan; Titescu, Gheorghe; Tamaian, Radu; Haulica, Ion; Bild, Walther

    2002-01-01

    The immunity booster is, according to its patent description, microbiologically pure water with an D/(D+H) isotopic concentration of 100 ppm, with physical-chemical characteristics similar to those of distilled water. It is obtained by sterilization of a mixture of deuterium depleted water, with a 25 ppm isotopic concentration, with distilled water in a volume ratio of 4:6. Unlike natural immunity boosters (bacterial agents as Bacillus Chalmette-Guerin, Corynebacterium parvum; lipopolysaccharides; human immunoglobulin) or synthetical products (levamysol; isoprinosyne with immunostimulating action), which cause hypersensitivity and shocks, thrill, fever, sickness and the immunity complex disease, the water of 100 ppm D/(D + H) isotopic concentration is a toxicity free product. The testing for immune reaction of the immunity booster led to the following results: - an increase of cell action capacity in the first immunity shielding stage (macrophages), as evidenced by stimulation of a number of essential characterizing parameters, as well as of the phagocytosis capacity, bactericide capacity, and opsonic capacity of serum; - an increase of the number of leucocyte particularly of the granulocyte in peripheral blood, produced especially when medullar toxic agents like caryolysine are used; - it hinders the effect of lowering the number of erythrocytes in peripheral blood produced by experimentally induced chronic inflammation; - an increase of nonspecific immunity defence capacity against specific bacterial aggression of both Gram-positive bacteria (Streptococcus pneumoniae 558 ) and of the Gram-negative ones (Klebsiella pneumoniae 507 ); - an increase of immunity - stimulating activity (proinflamatory), like that of levamisole as evidenced by the test of stimulation of experimentally induced inflammation by means of carrageenan. The following advantages of the immunity booster are stressed: - it is toxicity free and side effect free; - can be orally administrated as

  18. Calcitriol exerts an anti-tumor effect in osteosarcoma by inducing the endoplasmic reticulum stress response.

    Science.gov (United States)

    Shimizu, Takatsune; Kamel, Walied A; Yamaguchi-Iwai, Sayaka; Fukuchi, Yumi; Muto, Akihiro; Saya, Hideyuki

    2017-09-01

    Osteosarcoma is the most common type of primary bone tumor, and novel therapeutic approaches for this disease are urgently required. To identify effective agents, we screened a panel of Food and Drug Administration (FDA)-approved drugs in AXT cells, our newly established mouse osteosarcoma line, and identified calcitriol as a candidate compound with therapeutic efficacy for this disease. Calcitriol inhibited cell proliferation in AXT cells by blocking cell cycle progression. From a mechanistic standpoint, calcitriol induced endoplasmic reticulum (ER) stress, which was potentially responsible for downregulation of cyclin D1, activation of p38 MAPK, and intracellular production of reactive oxygen species (ROS). Knockdown of Atf4 or Ddit3 restored cell viability after calcitriol treatment, indicating that the ER stress response was indeed responsible for the anti-proliferative effect in AXT cells. Notably, the ER stress response was induced to a lesser extent in human osteosarcoma than in AXT cells, consistent with the weaker suppressive effect on cell growth in the human cells. Thus, the magnitude of ER stress induced by calcitriol might be an index of its anti-osteosarcoma effect. Although mice treated with calcitriol exhibited weight loss and elevated serum calcium levels, a single dose was sufficient to decrease osteosarcoma tumor size in vivo. Our findings suggest that calcitriol holds therapeutic potential for treatment of osteosarcoma, assuming that techniques to diminish its toxicity could be established. In addition, our results show that calcitriol could still be safely administered to osteosarcoma patients for its original purposes, including treatment of osteoporosis. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  19. The CD8⁺ T Cell-Mediated Immunity Induced by HPV-E6 Uploaded in Engineered Exosomes Is Improved by ISCOMATRIXTM Adjuvant.

    Science.gov (United States)

    Manfredi, Francesco; di Bonito, Paola; Ridolfi, Barbara; Anticoli, Simona; Arenaccio, Claudia; Chiozzini, Chiara; Baz Morelli, Adriana; Federico, Maurizio

    2016-11-09

    We recently described the induction of an efficient CD8⁺ T cell-mediated immune response against a tumor-associated antigen (TAA) uploaded in engineered exosomes used as an immunogen delivery tool. This immune response cleared tumor cells inoculated after immunization, and controlled the growth of tumors implanted before immunization. We looked for new protocols aimed at increasing the CD8⁺ T cell specific response to the antigen uploaded in engineered exosomes, assuming that an optimized CD8⁺ T cell immune response would correlate with a more effective depletion of tumor cells in the therapeutic setting. By considering HPV-E6 as a model of TAA, we found that the in vitro co-administration of engineered exosomes and ISCOMATRIX TM adjuvant, i.e., an adjuvant composed of purified ISCOPREP TM saponin, cholesterol, and phospholipids, led to a stronger antigen cross-presentation in both B- lymphoblastoid cell lines ( and monocyte-derived immature dendritic cells compared with that induced by the exosomes alone. Consistently, the co-inoculation in mice of ISCOMATRIX TM adjuvant and engineered exosomes induced a significant increase of TAA-specific CD8⁺ T cells compared to mice immunized with the exosomes alone. This result holds promise for effective usage of exosomes as well as alternative nanovesicles in anti-tumor therapeutic approaches.

  20. The CD8+ T Cell-Mediated Immunity Induced by HPV-E6 Uploaded in Engineered Exosomes Is Improved by ISCOMATRIXTM Adjuvant

    Science.gov (United States)

    Manfredi, Francesco; di Bonito, Paola; Ridolfi, Barbara; Anticoli, Simona; Arenaccio, Claudia; Chiozzini, Chiara; Baz Morelli, Adriana; Federico, Maurizio

    2016-01-01

    We recently described the induction of an efficient CD8+ T cell-mediated immune response against a tumor-associated antigen (TAA) uploaded in engineered exosomes used as an immunogen delivery tool. This immune response cleared tumor cells inoculated after immunization, and controlled the growth of tumors implanted before immunization. We looked for new protocols aimed at increasing the CD8+ T cell specific response to the antigen uploaded in engineered exosomes, assuming that an optimized CD8+ T cell immune response would correlate with a more effective depletion of tumor cells in the therapeutic setting. By considering HPV-E6 as a model of TAA, we found that the in vitro co-administration of engineered exosomes and ISCOMATRIXTM adjuvant, i.e., an adjuvant composed of purified ISCOPREPTM saponin, cholesterol, and phospholipids, led to a stronger antigen cross-presentation in both B- lymphoblastoid cell lines ( and monocyte-derived immature dendritic cells compared with that induced by the exosomes alone. Consistently, the co-inoculation in mice of ISCOMATRIXTM adjuvant and engineered exosomes induced a significant increase of TAA-specific CD8+ T cells compared to mice immunized with the exosomes alone. This result holds promise for effective usage of exosomes as well as alternative nanovesicles in anti-tumor therapeutic approaches. PMID:27834857

  1. Resistance to antitumor chemotherapy due to bounded-noise-induced transitions.

    Science.gov (United States)

    d'Onofrio, Alberto; Gandolfi, Alberto

    2010-12-01

    Tumor angiogenesis is a landmark of solid tumor development, but it is also directly relevant to chemotherapy. Indeed, the density and quality of neovessels may influence the effectiveness of therapies based on blood-born agents. In this paper, first we define a deterministic model of antiproliferative chemotherapy in which the drug efficacy is a unimodal function of vessel density, and then we show that under constant continuous infusion therapy the tumor-vessel system may be multistable. However, the actual drug concentration profiles are affected by bounded even if possibly large fluctuations. Through numerical simulations, we show that the tumor volume may undergo transitions to the higher equilibrium value induced by the bounded noise. In case of periodically delivered boli-based chemotherapy, we model the fluctuations due to time variability of both the drug clearance rate and the distribution volume, as well as those due to irregularities in drug delivery. We observed noise-induced transitions also in case of periodic delivering. By applying a time dense scheduling with constant average delivered drug (metronomic scheduling), we observed an easier suppression of the transitions. Finally, we propose to interpret the above phenomena as an unexpected non-genetic kind of resistance to chemotherapy.

  2. Systemic administration of an anti-tumor necrosis factor-alpha monoclonal antibody protects against endotoxin-induced uveitis in rats

    OpenAIRE

    Ge, Qingman; Wang, Shaocheng; Zheng, Yuezhong

    2016-01-01

    Objective: This study was to evaluate the effect of systemic injection of an anti-tumor necrosis factor alpha (TNF-?) monoclonal antibody (mAb) on endotoxin-induced uveitis (EIU). Materials and Methods: Fifty-six male Wistar rats (6?8 weeks old) were randomly divided into three groups: EIU, anti-TNF-? mAb + EIU, and control. EIU was induced by injecting Escherichia coli O55:B5 lipopolysaccharide (LPS) into the hind footpad of the rats (150 ?g/rat). The anti-TNF-? mAb (1 ?g/kg) was administrat...

  3. Antitumor Activity of Human Hydatid Cyst Fluid in a Murine Model of Colon Cancer

    Directory of Open Access Journals (Sweden)

    Edgardo Berriel

    2013-01-01

    Full Text Available This study evaluates the antitumor immune response induced by human hydatic cyst fluid (HCF in an animal model of colon carcinoma. We found that anti-HCF antibodies were able to identify cell surface and intracellular antigens in CT26 colon cancer cells. In prophylactic tumor challenge experiments, HCF vaccination was found to be protective against tumor formation for 40% of the mice (P=0.01. In the therapeutic setting, HCF vaccination induced tumor regression in 40% of vaccinated mice (P=0.05. This vaccination generated memory immune responses that protected surviving mice from tumor rechallenge, implicating the development of an adaptive immune response in this process. We performed a proteomic analysis of CT26 antigens recognized by anti-HCF antibodies to analyze the immune cross-reactivity between E. granulosus (HCF and CT26 colon cancer cells. We identified two proteins: mortalin and creatine kinase M-type. Interestingly, CT26 mortalin displays 60% homology with E. granulosus hsp70. In conclusion, our data demonstrate the capacity of HCF vaccination to induce antitumor immunity which protects from tumor growth in an animal model. This new antitumor strategy could open new horizons in the development of highly immunogenic anticancer vaccines.

  4. Immune disorders induced by exposure to pyrethroid insecticides

    Directory of Open Access Journals (Sweden)

    Justyna Skolarczyk

    2017-06-01

    Full Text Available Pyrethroids are biocides, which belong to the third generation of insecticides. They are used as biocides, insecticides and medicines. These agents react selectively, because they are less harmful to birds and mammals (due to poor intestinal absorption and rapid detoxification in the body of homeothermic organisms and they are poisonous for fish and insects.The aim of the article is to present the current state of knowledge on the effects of pyrethroids on the immune system based on the latest scientific research.The mechanism of action of pyrethroids include the delaying closure of voltage- sensitive sodium and chloride channels (including GABA- dependent channels. These compounds are neurotoxic.Studies have shown that they cause numerous immune disorders contributing to lowering of immunity in humans and animals. Exposure to pyrethroids can cause inhibition of proliferation of peripheral blood leukocytes and reducing the concentration of IgG immunolgobulines. They also cause reduced macrophages and decrease in interleukin 2 (IL-2, interleukin 8 (IL-8, interleukin 12p70 (IL-12p70, and interferon γ (IFN-γ. Some of these compounds cause increase of liver weight and increase of bone marrow cellularity, and may induce apoptosis of the thymus. Pyrethroids can cause allergies and asthma. Their immunosuppressive effects can impair host resistance against infections. Exposure to these compounds can also contribute to induction of the cancer, especially in patients with impaired immune function.

  5. Immune disorders induced by exposure to pyrethroid insecticides.

    Science.gov (United States)

    Skolarczyk, Justyna; Pekar, Joanna; Nieradko-Iwanicka, Barbara

    2017-06-08

    Pyrethroids are biocides, which belong to the third generation of insecticides. They are used as biocides, insecticides and medicines. These agents react selectively, because they are less harmful to birds and mammals (due to poor intestinal absorption and rapid detoxification in the body of homeothermic organisms) and they are poisonous for fish and insects. The aim of the article is to present the current state of knowledge on the effects of pyrethroids on the immune system based on the latest scientific research. The mechanism of action of pyrethroids include the delaying closure of voltage- sensitive sodium and chloride channels (including GABA- dependent channels). These compounds are neurotoxic. Studies have shown that they cause numerous immune disorders contributing to lowering of immunity in humans and animals. Exposure to pyrethroids can cause inhibition of proliferation of peripheral blood leukocytes and reducing the concentration of IgG immunolgobulines. They also cause reduced macrophages and decrease in interleukin 2 (IL-2), interleukin 8 (IL-8), interleukin 12p70 (IL-12p70), and interferon γ (IFN-γ). Some of these compounds cause increase of liver weight and increase of bone marrow cellularity, and may induce apoptosis of the thymus. Pyrethroids can cause allergies and asthma. Their immunosuppressive effects can impair host resistance against infections. Exposure to these compounds can also contribute to induction of the cancer, especially in patients with impaired immune function.

  6. Immunization with truncated envelope protein of Zika virus induces protective immune response in mice.

    Science.gov (United States)

    Han, Jian-Feng; Qiu, Yang; Yu, Jiu-Yang; Wang, Hong-Jiang; Deng, Yong-Qiang; Li, Xiao-Feng; Zhao, Hui; Sun, Han-Xiao; Qin, Cheng-Feng

    2017-08-30

    The global spread of Zika virus (ZIKV) as well as its unexpected link to infant microcephaly have resulted in serious public health concerns. No antiviral drugs against ZIKV is currently available, and vaccine development is of high priority to prepare for potential ZIKV pandemic. In the present study, a truncated E protein with the N-terminal 90% region reserved (E90) from a contemporary ZIKV strain was cloned and expressed in Escherichia coli, purified by a Ni-NTA column, and characterized by Western blotting assays. Immunization with recombinant E90 induced robust ZIKV-specific humoral response in adult BALB/c mice. Passive transfer of the antisera from E90-immunized mice conferred full protection against lethal ZIKV challenge in a neonatal mice model. Our results indicate that recombinant ZIKV E90 described here represents as a promising ZIKV subunit vaccine that deserves further clinical development.

  7. Impact of Depleting Therapeutic Monoclonal Antibodies on the Host Adaptive Immunity: A Bonus or a Malus?

    Directory of Open Access Journals (Sweden)

    Claire Deligne

    2017-08-01

    Full Text Available Clinical responses to anti-tumor monoclonal antibody (mAb treatment have been regarded for many years only as a consequence of the ability of mAbs to destroy tumor cells by innate immune effector mechanisms. More recently, it has also been shown that anti-tumor antibodies can induce a long-lasting anti-tumor adaptive immunity, likely responsible for durable clinical responses, a phenomenon that has been termed the vaccinal effect of antibodies. However, some of these anti-tumor antibodies are directed against molecules expressed both by tumor cells and normal immune cells, in particular lymphocytes, and, hence, can also strongly affect the host adaptive immunity. In addition to a delayed recovery of target cells, lymphocyte depleting-mAb treatments can have dramatic consequences on the adaptive immune cell network, its rebound, and its functional capacities. Thus, in this review, we will not only discuss the mAb-induced vaccinal effect that has emerged from experimental preclinical studies and clinical trials but also the multifaceted impact of lymphocytes-depleting therapeutic antibodies on the host adaptive immunity. We will also discuss some of the molecular and cellular mechanisms of action whereby therapeutic mAbs induce a long-term protective anti-tumor effect and the relationship between the mAb-induced vaccinal effect and the immune response against self-antigens.

  8. Antitumor Allium Sulfides.

    Science.gov (United States)

    Nohara, Toshihiro; Fujiwara, Yukio; El-Aasr, Mona; Ikeda, Tsuyoshi; Ono, Masateru; Nakano, Daisuke; Kinjo, Junei

    2017-01-01

    We examined the sulfides in onion (Allium cepa L.), Welsh onion (A. fistulosum L.), and garlic (A. sativum L.), and obtained three new thiolane-type sulfides (onionins A 1 -A 3 ) from onion; two new thiabicyclic-type sulfides (welsonins A 1 , A 2 ), together with onionins A 1 -A 3 , from Welsh onion; and six new acyclic-type sulfides (garlicnins L-1-L-4, E, and F), ten new thiolane-type sulfides (garlicnins A, B 1 -B 4 , C 1 -C 3 , K 1 , and K 2 ), and three new atypical cyclic-type sulfides (garlicnins G, I, and J) from garlic. Acetone extracts showed the potential of these sulfides in inhibiting the polarization of M2 activated macrophages that are capable of suppressing tumor-cell proliferation. The effect of the thiolane-type sulfide of a major component, onionin A 1 , on tumor progression and metastasis in both osteosarcoma and ovarian cancer-bearing mouse models was then examined. Tumor proliferation was depressed, and tumor metastasis was controlled by regulating macrophage activation. These results showed that onionin A 1 is an effective agent for controlling tumors in both in vitro and in vivo models, and that the antitumor effects observed in vivo are likely caused by reversing the antitumor immune system. Activation of the antitumor immune system by onionin A 1 might be an effective adjuvant therapy for patients with osteosarcoma, ovarian cancer and other malignant tumors. Based on these findings, pharmacological investigations will be conducted in the future to develop natural and healthy foods and anti-cancer agents that can prevent or combat disease.

  9. Antitumor enhancement by adoptive transfer of tumor antigen primed, inactivated MHC-haploidentical lymphocytes.

    Science.gov (United States)

    Shi, Guilan; Zhou, Chunxia; Wang, Dongmei; Ma, Wenbo; Liu, Binlei; Zhang, Shuren

    2014-02-01

    The present study investigated the antitumor effects by adoptive transfer of tumor antigen primed, inactivated MHC-haploidentical lymphocytes in TC-1 lung cancer mouse model. Our studies revealed that the inactivated MHC-haploidentical effecter cells display the antitumor activity in vitro and target the tumor in vivo. After adoptive transferring these effecter cells, the Th1 cytokines such as IL-2 and IFN-γ are elevated in the serum; the recipient tumor-specific cytotoxic T-cells and natural killer cells are activated; tumor specific memory T cells are induced; tumor growth is inhibited and mouse survival is prolonged. The results indicate that MHC-haploidentical lymphocytes provide both effecter cells which can target the tumor cells through the identical MHC molecules and an adjuvant effects through the unmatched allogeneic MHC molecules which induces endogenous innate and adaptive antitumor immune responses. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  10. Influenza vaccine induces intracellular immune memory of human NK cells.

    Science.gov (United States)

    Dou, Yaling; Fu, Binqing; Sun, Rui; Li, Wenting; Hu, Wanfu; Tian, Zhigang; Wei, Haiming

    2015-01-01

    Influenza vaccines elicit antigen-specific antibodies and immune memory to protect humans from infection with drift variants. However, what supports or limits vaccine efficacy and duration is unclear. Here, we vaccinated healthy volunteers with annual vaccine formulations and investigated the dynamics of T cell, natural killer (NK) cell and antibody responses upon restimulation with heterologous or homologous influenza virus strains. Influenza vaccines induced potential memory NK cells with increased antigen-specific recall IFN-γ responses during the first 6 months. In the absence of significant changes in other NK cell markers (CD45RO, NKp44, CXCR6, CD57, NKG2C, CCR7, CD62L and CD27), influenza vaccines induced memory NK cells with the distinct feature of intracellular NKp46 expression. Indeed, surface NKp46 was internalized, and the dynamic increase in NKp46(intracellular)+CD56dim NK cells positively correlated with increased IFN-γ production to influenza virus restimulation after vaccination. In addition, anti-NKp46 antibodies blocked IFN-γ responses. These findings provide insights into a novel mechanism underlying vaccine-induced immunity and NK-related diseases, which may help to design persisting and universal vaccines in the future.

  11. Personalized peptide vaccine-induced immune response associated with long-term survival of a metastatic cholangiocarcinoma patient.

    Science.gov (United States)

    Löffler, Markus W; Chandran, P Anoop; Laske, Karoline; Schroeder, Christopher; Bonzheim, Irina; Walzer, Mathias; Hilke, Franz J; Trautwein, Nico; Kowalewski, Daniel J; Schuster, Heiko; Günder, Marc; Carcamo Yañez, Viviana A; Mohr, Christopher; Sturm, Marc; Nguyen, Huu-Phuc; Riess, Olaf; Bauer, Peter; Nahnsen, Sven; Nadalin, Silvio; Zieker, Derek; Glatzle, Jörg; Thiel, Karolin; Schneiderhan-Marra, Nicole; Clasen, Stephan; Bösmüller, Hans; Fend, Falko; Kohlbacher, Oliver; Gouttefangeas, Cécile; Stevanović, Stefan; Königsrainer, Alfred; Rammensee, Hans-Georg

    2016-10-01

    We report a novel experimental immunotherapeutic approach in a patient with metastatic intrahepatic cholangiocarcinoma. In the 5year course of the disease, the initial tumor mass, two local recurrences and a lung metastasis were surgically removed. Lacking alternative treatment options, aiming at the induction of anti-tumor T cells responses, we initiated a personalized multi-peptide vaccination, based on in-depth analysis of tumor antigens (immunopeptidome) and sequencing. Tumors were characterized by immunohistochemistry, next-generation sequencing and mass spectrometry of HLA ligands. Although several tumor-specific neo-epitopes were predicted in silico, none could be validated by mass spectrometry. Instead, a personalized multi-peptide vaccine containing non-mutated tumor-associated epitopes was designed and applied. Immunomonitoring showed vaccine-induced T cell responses to three out of seven peptides administered. The pulmonary metastasis resected after start of vaccination showed strong immune cell infiltration and perforin positivity, in contrast to the previous lesions. The patient remains clinically healthy, without any radiologically detectable tumors since March 2013 and the vaccination is continued. This remarkable clinical course encourages formal clinical studies on adjuvant personalized peptide vaccination in cholangiocarcinoma. Metastatic cholangiocarcinomas, cancers that originate from the liver bile ducts, have very limited treatment options and a fatal prognosis. We describe a novel therapeutic approach in such a patient using a personalized multi-peptide vaccine. This vaccine, developed based on the characterization of the patient's tumor, evoked detectable anti-tumor immune responses, associating with long-term tumor-free survival. Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  12. Persistence of the immune response induced by BCG vaccination

    Directory of Open Access Journals (Sweden)

    Blitz Rose

    2008-01-01

    Full Text Available Abstract Background Although BCG vaccination is recommended in most countries of the world, little is known of the persistence of BCG-induced immune responses. As novel TB vaccines may be given to boost the immunity induced by neonatal BCG vaccination, evidence concerning the persistence of the BCG vaccine-induced response would help inform decisions about when such boosting would be most effective. Methods A randomised control study of UK adolescents was carried out to investigate persistence of BCG immune responses. Adolescents were tested for interferon-gamma (IFN-γ response to Mycobacterium tuberculosis purified protein derivative (M.tb PPD in a whole blood assay before, 3 months, 12 months (n = 148 and 3 years (n = 19 after receiving teenage BCG vaccination or 14 years after receiving infant BCG vaccination (n = 16. Results A gradual reduction in magnitude of response was evident from 3 months to 1 year and from 1 year to 3 years following teenage vaccination, but responses 3 years after vaccination were still on average 6 times higher than before vaccination among vaccinees. Some individuals (11/86; 13% failed to make a detectable antigen-specific response three months after vaccination, or lost the response after 1 (11/86; 13% or 3 (3/19; 16% years. IFN-γ response to Ag85 was measured in a subgroup of adolescents and appeared to be better maintained with no decline from 3 to 12 months. A smaller group of adolescents were tested 14 years after receiving infant BCG vaccination and 13/16 (81% made a detectable IFN-γ response to M.tb PPD 14 years after infant vaccination as compared to 6/16 (38% matched unvaccinated controls (p = 0.012; teenagers vaccinated in infancy were 19 times more likely to make an IFN-γ response of > 500 pg/ml than unvaccinated teenagers. Conclusion BCG vaccination in infancy and adolescence induces immunological memory to mycobacterial antigens that is still present and measurable for at least 14 years in the

  13. Advances of Immune Checkpoint Inhibitors in Tumor Immunotherapy

    Science.gov (United States)

    Guo, Qiao

    2018-01-01

    Immune checkpoints are cell surface molecules that can fine-tune the immune responses, they are crucial for modulating the duration and amplitude of immune reactions while maintaining self-tolerance in order to minimize autoimmune responses. Numerous studies have demonstrated that tumors cells can directly express immune-checkpoint molecules, or induce many inhibitory molecules expression in the tumor microenvironment to inhibit the anti-tumor immunity. Releasing these brakes has emerged as an exciting strategy to cure cancer. In the past few years, clinical trials with therapeutic antibodies targeting to the checkpoint molecules CTLA-4 and PD-1 have rekindled the hope for cancer immunotherapy. In contrast to the conventional treatment, checkpoint inhibitors induce broad and durable antitumor responses. In the future, treatment may involve combination therapy to target different checkpoint molecules and stages of the adaptive immune responses. In this review, we summarized the recent advances of the study and development of other checkpoint molecules in tumor immunotherapy.

  14. Increasing the immune activity of exosomes: the effect of miRNA-depleted exosome proteins on activating dendritic cell/cytokine-induced killer cells against pancreatic cancer* #

    Science.gov (United States)

    Que, Ri-sheng; Lin, Cheng; Ding, Guo-ping; Wu, Zheng-rong; Cao, Li-ping

    2016-01-01

    Background: Tumor-derived exosomes were considered to be potential candidates for tumor vaccines because they are abundant in immune-regulating proteins, whereas tumor exosomal miRNAs may induce immune tolerance, thereby having an opposite immune function. Objective: This study was designed to separate exosomal protein and depleted exosomal microRNAs (miRNAs), increasing the immune activity of exosomes for activating dendritic cell/cytokine-induced killer cells (DC/CIKs) against pancreatic cancer (PC). Methods: PC-derived exosomes (PEs) were extracted from cultured PANC-1 cell supernatants and then ruptured; this was followed by ultrafiltered exosome lysates (UELs). DCs were stimulated with lipopolysaccharide (LPS), PE, and UEL, followed by co-culture with CIKs. The anti-tumor effects of DC/CIKs against PC were evaluated by proliferation and killing rates, tumor necrosis factor-α (TNF-α) and perforin secretion. Exosomal miRNAs were depleted after lysis and ultrafiltration, while 128 proteins were retained, including several immune-activating proteins. Results: UEL-stimulated DC/CIKs showed a higher killing rate than LPS- and PE-stimulated DC/CIKs. Conclusions: miRNA-depleted exosome proteins may be promising agonists for specifically activating DC/CIKs against PC. PMID:27143262

  15. Increasing the immune activity of exosomes: the effect of miRNA-depleted exosome proteins on activating dendritic cell/cytokine-induced killer cells against pancreatic cancer.

    Science.gov (United States)

    Que, Ri-Sheng; Lin, Cheng; Ding, Guo-Ping; Wu, Zheng-Rong; Cao, Li-Ping

    2016-05-01

    Tumor-derived exosomes were considered to be potential candidates for tumor vaccines because they are abundant in immune-regulating proteins, whereas tumor exosomal miRNAs may induce immune tolerance, thereby having an opposite immune function. This study was designed to separate exosomal protein and depleted exosomal microRNAs (miRNAs), increasing the immune activity of exosomes for activating dendritic cell/cytokine-induced killer cells (DC/CIKs) against pancreatic cancer (PC). PC-derived exosomes (PEs) were extracted from cultured PANC-1 cell supernatants and then ruptured; this was followed by ultrafiltered exosome lysates (UELs). DCs were stimulated with lipopolysaccharide (LPS), PE, and UEL, followed by co-culture with CIKs. The anti-tumor effects of DC/CIKs against PC were evaluated by proliferation and killing rates, tumor necrosis factor-α (TNF-α) and perforin secretion. Exosomal miRNAs were depleted after lysis and ultrafiltration, while 128 proteins were retained, including several immune-activating proteins. UEL-stimulated DC/CIKs showed a higher killing rate than LPS- and PE-stimulated DC/CIKs. miRNA-depleted exosome proteins may be promising agonists for specifically activating DC/CIKs against PC.

  16. Alemtuzumab-induced elimination of HIV-1-infected immune cells.

    Science.gov (United States)

    Ruxrungtham, Kiat; Sirivichayakul, Sunee; Buranapraditkun, Supranee; Krause, Werner

    2016-01-01

    Currently, there is no drug known that is able to eradicate either HIV or HIV-infected host cells. The effectiveness of all available treatments is based on the prevention of viral replication. We investigated whether the monoclonal, CD52 receptor-targeting antibody, alemtuzumab, which is currently approved for the treatment of multiple sclerosis, is able to eliminate HIV-infected immune cells. In blood samples from healthy donors and from HIV-1-infected subjects who were either treatment-naïve or resistant to HAART, we studied whether the CD52 expression on T cells and their subsets (CD3, CD4, CD8), B cells (CD19), dendritic cells (CD123) and monocytes (CD11c) is retained in HIV-1 infection and whether alemtuzumab is able to eradicate infected cells, using four-colour flow cytometry. We found that CD52 expression on immune cells is retained in HIV-1 infection regardless of CD4 cell count, viral load and treatment status, and is amenable to alemtuzumab-induced depletion. For the first time it could be shown in vitro that HIV-1-infected immune cells can be eliminated by using the monoclonal antibody alemtuzumab.

  17. Andrographolide enhanced 5-fluorouracil-induced antitumor effect in colorectal cancer via inhibition of c-MET pathway

    Directory of Open Access Journals (Sweden)

    Su M

    2017-11-01

    Full Text Available Meng Su,1 Baoli Qin,1 Fang Liu,2 Yuze Chen,2 Rui Zhang2 1Department of Internal Medicine, 2Department of Colorectal Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Liaoning, China Abstract: Colorectal cancer (CRC is the third most common malignant neoplasm worldwide. 5-Fluorouracil (5-Fu is the most important chemotherapeutic drug used for the treatment of CRC. However, resistance to 5-Fu therapies is a growing concern in CRC clinical practice recently. Andrographolide (Andro is a main bioactive constituent of the herb Andrographis paniculata, which has various biological effects including anti-inflammation and antitumor activities. In the present study, we investigated the effects of combined Andro with 5-Fu against CRC HCT-116 cells. In vitro studies showed that Andro synergistically enhanced the anti-proliferation effect of 5-Fu on HCT-116 cells due to increased apoptotic cells. Meanwhile, results of the enzyme linked immunosorbent assay indicated that the level of phosphorylated cellular-mesenchymal to epithelial transition factor (p-MET was decreased by the combination treatment. Further study suggested that Andro promoted the antitumor effect of 5-Fu by downregulating the level of p-MET. In conclusion, these results confirmed the synergistic antitumor activity of Andro on CRC and provide evidence for possible clinical application of Andro for enhancing the antitumor effect of 5-Fu in CRC treatment. Keywords: Andro, 5-Fu, HCT-116 cells, apoptosis, p-MET

  18. The tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20) imposes a brake on antitumor activity of CD8 T cells.

    Science.gov (United States)

    Giordano, Marilyn; Roncagalli, Romain; Bourdely, Pierre; Chasson, Lionel; Buferne, Michel; Yamasaki, Sho; Beyaert, Rudi; van Loo, Geert; Auphan-Anezin, Nathalie; Schmitt-Verhulst, Anne-Marie; Verdeil, Grégory

    2014-07-29

    The transcription factor NF-κB is central to inflammatory signaling and activation of innate and adaptive immune responses. Activation of the NF-κB pathway is tightly controlled by several negative feedback mechanisms, including A20, an ubiquitin-modifying enzyme encoded by the tnfaip3 gene. Mice with selective deletion of A20 in myeloid, dendritic, or B cells recapitulate some human inflammatory pathology. As we observed high expression of A20 transcripts in dysfunctional CD8 T cells in an autochthonous melanoma, we analyzed the role of A20 in regulation of CD8 T-cell functions, using mice in which A20 was selectively deleted in mature conventional T cells. These mice developed lymphadenopathy and some organ infiltration by T cells but no splenomegaly and no detectable pathology. A20-deleted CD8 T cells had increased sensitivity to antigen stimulation with production of large amounts of IL-2 and IFNγ, correlated with sustained nuclear expression of NF-κB components reticuloendotheliosis oncogene c-Rel and p65. Overexpression of A20 by retroviral transduction of CD8 T cells dampened their intratumor accumulation and antitumor activity. In contrast, relief from the A20 brake in NF-κB activation in adoptively transferred antitumor CD8 T cells led to improved control of melanoma growth. Tumor-infiltrating A20-deleted CD8 T cells had enhanced production of IFNγ and TNFα and reduced expression of the inhibitory receptor programmed cell death 1. As manipulation of A20 expression in CD8 T cells did not result in pathologic manifestations in the mice, we propose it as a candidate to be targeted to increase antitumor efficiency of adoptive T-cell immunotherapy.

  19. Different protein of Echinococcus granulosus stimulates dendritic induced immune response.

    Science.gov (United States)

    Wang, Yana; Wang, Qiang; Lv, Shiyu; Zhang, Shengxiang

    2015-06-01

    Cystic echinococcosis is a chronic infectious disease that results from a host/parasite interaction. Vaccination with ferritin derived from Echinococcus granulosus is a potential preventative treatment. To understand whether ferritin is capable of inducing a host immune response, we investigated the response of dendritic cells (DCs) to both recombinant ferritin protein and the hydatid fluid (HF) of E. granulosus. We evaluated the immunomodulatory potential of these antigens by performing, immunocytochemistry, electron microscopy and in vivo imaging of monocyte-derived murine DCs. During antigen stimulation of DCs, ferritin cause DCs maturation and induced higher levels of surface marker expression and activated T-cell proliferation and migration. On contrary, HF failed to induce surface marker expression and to stimulate T-cell proliferation. In response to HF, DCs produced interleukin-6 (IL-6), but no IL-12 and IL-10. DCs stimulated with ferritin produced high levels of cytokines. Overall, HF appears to induce host immunosuppression in order to ensure parasite survival via inhibits DC maturation and promotes Th2-dependent secretion of cytokines. Although ferritin also promoted DC maturation and cytokine release, it also activates CD4+T-cell proliferation, but regard of the mechanism of the Eg.ferritin induce host to eradicate E. granulosus were not clear.

  20. Candesartan ameliorates impaired fear extinction induced by innate immune activation.

    Science.gov (United States)

    Quiñones, María M; Maldonado, Lizette; Velazquez, Bethzaly; Porter, James T

    2016-02-01

    Patients with post-traumatic stress disorder (PTSD) tend to show signs of a relatively increased inflammatory state suggesting that activation of the immune system may contribute to the development of PTSD. In the present study, we tested whether activation of the innate immune system can disrupt acquisition or recall of auditory fear extinction using an animal model of PTSD. Male adolescent rats received auditory fear conditioning in context A. The next day, an intraperitoneal injection of lipopolysaccharide (LPS; 100 μg/kg) prior to auditory fear extinction in context B impaired acquisition and recall of extinction. LPS (100 μg/kg) given after extinction training did not impair extinction recall suggesting that LPS did not affect consolidation of extinction. In contrast to cued fear extinction, contextual fear extinction was not affected by prior injection of LPS (100 μg/kg). Although LPS also reduced locomotion, we could dissociate the effects of LPS on extinction and locomotion by using a lower dose of LPS (50 μg/kg) which impaired locomotion without affecting extinction. In addition, 15 h after an injection of 250 μg/kg LPS in adult rats, extinction learning and recall were impaired without affecting locomotion. A sub-chronic treatment with candesartan, an angiotensin II type 1 receptor blocker, prevented the LPS-induced impairment of extinction in adult rats. Our results demonstrate that activation of the innate immune system can disrupt auditory fear extinction in adolescent and adult animals. These findings also provide direction for clinical studies of novel treatments that modulate the innate immune system for stress-related disorders like PTSD. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. A mosquito mediator of parasite-induced immune priming.

    Science.gov (United States)

    Simões, Maria L; Dimopoulos, George

    2015-09-01

    Immune memory is a central feature of the mammalian adaptive immune system. The more primitive innate immune system of insects has also been shown to comprise memory, or immune priming. A recent study has shed new light on how Plasmodium primes the mosquito immune system for greater resistance to a subsequent infection with the same pathogen. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. Sublingual immunization with a live attenuated influenza a virus lacking the nonstructural protein 1 induces broad protective immunity in mice.

    Directory of Open Access Journals (Sweden)

    Hae-Jung Park

    Full Text Available The nonstructural protein 1 (NS1 of influenza A virus (IAV enables the virus to disarm the host cell type 1 IFN defense system. Mutation or deletion of the NS1 gene leads to attenuation of the virus and enhances host antiviral response making such live-attenuated influenza viruses attractive vaccine candidates. Sublingual (SL immunization with live influenza virus has been found to be safe and effective for inducing protective immune responses in mucosal and systemic compartments. Here we demonstrate that SL immunization with NS1 deleted IAV (DeltaNS1 H1N1 or DeltaNS1 H5N1 induced protection against challenge with homologous as well as heterosubtypic influenza viruses. Protection was comparable with that induced by intranasal (IN immunization and was associated with high levels of virus-specific antibodies (Abs. SL immunization with DeltaNS1 virus induced broad Ab responses in mucosal and systemic compartments and stimulated immune cells in mucosa-associated and systemic lymphoid organs. Thus, SL immunization with DeltaNS1 offers a novel potential vaccination strategy for the control of influenza outbreaks including pandemics.

  3. Sublingual immunization with a live attenuated influenza a virus lacking the nonstructural protein 1 induces broad protective immunity in mice.

    Science.gov (United States)

    Park, Hae-Jung; Ferko, Boris; Byun, Young-Ho; Song, Joo-Hye; Han, Gye-Yeong; Roethl, Elisabeth; Egorov, Andrej; Muster, Thomas; Seong, Baiklin; Kweon, Mi-Na; Song, Manki; Czerkinsky, Cecil; Nguyen, Huan H

    2012-01-01

    The nonstructural protein 1 (NS1) of influenza A virus (IAV) enables the virus to disarm the host cell type 1 IFN defense system. Mutation or deletion of the NS1 gene leads to attenuation of the virus and enhances host antiviral response making such live-attenuated influenza viruses attractive vaccine candidates. Sublingual (SL) immunization with live influenza virus has been found to be safe and effective for inducing protective immune responses in mucosal and systemic compartments. Here we demonstrate that SL immunization with NS1 deleted IAV (DeltaNS1 H1N1 or DeltaNS1 H5N1) induced protection against challenge with homologous as well as heterosubtypic influenza viruses. Protection was comparable with that induced by intranasal (IN) immunization and was associated with high levels of virus-specific antibodies (Abs). SL immunization with DeltaNS1 virus induced broad Ab responses in mucosal and systemic compartments and stimulated immune cells in mucosa-associated and systemic lymphoid organs. Thus, SL immunization with DeltaNS1 offers a novel potential vaccination strategy for the control of influenza outbreaks including pandemics.

  4. Radiation-Induced Immune Modulation in Prostate Cancer

    National Research Council Canada - National Science Library

    McBride, William H

    2008-01-01

    Radiotherapy is generally considered to be immunosuppressive, whereas we hypothesized that it modulates immune responses and has profound effects on the immune system rather than eliminating of lymphocytes...

  5. Epigenetic regulation of inducible gene expression in the immune system.

    Science.gov (United States)

    Lim, Pek Siew; Li, Jasmine; Holloway, Adele F; Rao, Sudha

    2013-07-01

    T cells are exquisitely poised to respond rapidly to pathogens and have proved an instructive model for exploring the regulation of inducible genes. Individual genes respond to antigenic stimulation in different ways, and it has become clear that the interplay between transcription factors and the chromatin platform of individual genes governs these responses. Our understanding of the complexity of the chromatin platform and the epigenetic mechanisms that contribute to transcriptional control has expanded dramatically in recent years. These mechanisms include the presence/absence of histone modification marks, which form an epigenetic signature to mark active or inactive genes. These signatures are dynamically added or removed by epigenetic enzymes, comprising an array of histone-modifying enzymes, including the more recently recognized chromatin-associated signalling kinases. In addition, chromatin-remodelling complexes physically alter the chromatin structure to regulate chromatin accessibility to transcriptional regulatory factors. The advent of genome-wide technologies has enabled characterization of the chromatin landscape of T cells in terms of histone occupancy, histone modification patterns and transcription factor association with specific genomic regulatory regions, generating a picture of the T-cell epigenome. Here, we discuss the multi-layered regulation of inducible gene expression in the immune system, focusing on the interplay between transcription factors, and the T-cell epigenome, including the role played by chromatin remodellers and epigenetic enzymes. We will also use IL2, a key inducible cytokine gene in T cells, as an example of how the different layers of epigenetic mechanisms regulate immune responsive genes during T-cell activation. © 2013 John Wiley & Sons Ltd.

  6. Platelet-derived MHC class I confers a pseudonormal phenotype to cancer cells that subverts the antitumor reactivity of natural killer immune cells.

    Science.gov (United States)

    Placke, Theresa; Örgel, Melanie; Schaller, Martin; Jung, Gundram; Rammensee, Hans-Georg; Kopp, Hans-Georg; Salih, Helmut Rainer

    2012-01-15

    Natural killer (NK) cells are cytotoxic lymphocytes that play an important role in tumor immunosurveillance, preferentially eliminating targets with low or absent expression of MHC class I and stress-induced expression of ligands for activating NK receptors. Platelets promote metastasis by protecting disseminating tumor cells from NK cell immunosurveillance, but the underlying mechanisms are not well understood. In this study, we show that tumor cells rapidly get coated in the presence of platelets in vitro, and circulating tumor cells of cancer patients display coexpression of platelet markers. Flow cytometry, immunofluorescent staining, confocal microscopy, and analyses on an ultrastructural level using immunoelectron microscopy revealed that such coating may cause transfer of MHC class I onto the tumor cell surface resulting in high-level expression of platelet-derived normal MHC class I. The resulting "phenotype of false pretenses" disrupts recognition of tumor cell missing self, thereby impairing cytotoxicity and IFN-γ production by NK cells. Thus, our data indicate that platelets, by conferring an unsuspicious "pseudonormal" phenotype, may enable a molecular mimicry that allows metastasizing tumor cells to downregulate MHC class I, to escape T-cell-mediated immunity without inducing susceptibility to NK cell reactivity.

  7. The anti-tumor effect of bee honey in Ehrlich ascite tumor model of mice is coincided with stimulation of the immune cells.

    Science.gov (United States)

    Attia, W Y; Gabry, M S; El-Shaikh, K A; Othman, G A

    2008-01-01

    Honey is thought to exhibit a broad spectrum of therapeutic properties including antibacterial, antifungal, cytostatic and anti-inflammatory activity and has been used for the treatment of gastric ulcers, burns, and for storage of skin grafts. The present study investigated the antitumor effect of bee honey against Ehrlich ascites tumor in mice and the possible mode of antitumor action. Peroral administration of mice with honey (10, 100 or 1000 mg/ 100 g BW) every other day for 4 weeks before intraperitoneal inoculation with Ehrlich ascites tumor (EAT, 1 x 10(6) cells) increased the number bone marrow cells as well as peritoneal macrophages, but not peripheral blood leukocytes nor splenocytes. The phagocytic function of macrophages as well as the T- and B-cell functions were also increased. Honey pre-treatment also recovered the total lipids, total proteins, as well as liver and kidney enzyme activities in EAT-bearing mice. In vitro studies on EAT cells demonstrated inhibitory effect of honey on tumor cell proliferation, viability % of tumor cells as well as the size of solid tumor. The present results indicate that the preventive treatment with honey is considerably effective against EAT in mice both in vivo and in vitro. The antitumor activity of honey may occur through the activation of macrophages, T-cells and B-cells.

  8. Metallothionein expression in mouse immune organ induced by radiation

    International Nuclear Information System (INIS)

    Ju Guizhi; Fan Cai; Liu Shuzheng

    2000-01-01

    To explore the effect of ionizing radiation on the expression of metallothionein (MT) in immune organs, the 109 Cd-haemoglobin affinity assay was employed to measure the content of MT in tissues. The dose effect relationship of the MT expression in mouse thymus and spleen was investigated 16h after exposure to 0.5, 1, 2, 4 and 6 Gy whole body irradiation (WBI). And the time course changes in MT expression in mouse thymus and spleen were also determined at different time intervals after 4 Gy WBI. The results showed that the MT content in mouse thymus was significantly increased 16 h after 4 Gy and 6 Gy irradiation compared with that in sham-irradiated mice (p < 0.05, respectively). And it was found that the MT content in mouse thymus was also increased significantly from 8 h to 48 h after 4 Gy irradiation compared with that in sham-irradiated mice (p < 0.05 - p < 0.001). However, there were no markedly changes for the MT expression in the mouse spleen after exposure to X rays. These results mentioned above suggest that the MT expression in immune organs could be induced by X rays, which may be tissue-specific

  9. Steric-electronic effects in malarial peptides inducing sterile immunity

    Energy Technology Data Exchange (ETDEWEB)

    Moreno-Vranich, Armando [Fundacion Instituto de Inmunologia de Colombia (FIDIC), Bogota (Colombia); Patarroyo, Manuel E., E-mail: mepatarr@mail.com [Fundacion Instituto de Inmunologia de Colombia (FIDIC), Bogota (Colombia); Universidad Nacional de Colombia, Bogota (Colombia)

    2012-07-13

    Highlights: Black-Right-Pointing-Pointer Is it evident that the residues position are relevant regarding of {phi} angular value. Black-Right-Pointing-Pointer The geometry considered for detailing the alterations undergone by HABPs. Black-Right-Pointing-Pointer The inter planar interactions ruled by clashes between the atoms making them up. -- Abstract: Conserved Plasmodium falciparum high activity binding peptides' (HABPs) most relevant proteins involved in malaria parasite invasion are immunologically silent; critical binding residues must therefore be specifically replaced to render them highly immunogenic and protection-inducing. Such changes have a tremendous impact on these peptides' steric-electronic effects, such as modifications to peptide length peptide bonds and electronic orbitals' disposition, to allow a better fit into immune system MHCII molecules and better interaction with the TCR which might account for the final immunological outcome.

  10. Polar Lipids of Burkholderia pseudomallei Induce Different Host Immune Responses

    Science.gov (United States)

    Gonzalez-Juarrero, Mercedes; Mima, Naoko; Trunck, Lily A.; Schweizer, Herbert P.; Bowen, Richard A.; Dascher, Kyle; Mwangi, Waithaka; Eckstein, Torsten M.

    2013-01-01

    Melioidosis is a disease in tropical and subtropical regions of the world that is caused by Burkholderia pseudomallei. In endemic regions the disease occurs primarily in humans and goats. In the present study, we used the goat as a model to dissect the polar lipids of B. pseudomallei to identify lipid molecules that could be used for adjuvants/vaccines or as diagnostic tools. We showed that the lipidome of B. pseudomallei and its fractions contain several polar lipids with the capacity to elicit different immune responses in goats, namely rhamnolipids and ornithine lipids which induced IFN-γ, whereas phospholipids and an undefined polar lipid induced strong IL-10 secretion in CD4+ T cells. Autologous T cells co-cultured with caprine dendritic cells (cDCs) and polar lipids of B. pseudomallei proliferated and up-regulated the expression of CD25 (IL-2 receptor) molecules. Furthermore, we demonstrated that polar lipids were able to up-regulate CD1w2 antigen expression in cDCs derived from peripheral blood monocytes. Interestingly, the same polar lipids had only little effect on the expression of MHC class II DR antigens in the same caprine dendritic cells. Finally, antibody blocking of the CD1w2 molecules on cDCs resulted in decreased expression for IFN-γ by CD4+ T cells. Altogether, these results showed that polar lipids of B. pseudomallei are recognized by the caprine immune system and that their recognition is primarily mediated by the CD1 antigen cluster. PMID:24260378

  11. Polar lipids of Burkholderia pseudomallei induce different host immune responses.

    Directory of Open Access Journals (Sweden)

    Mercedes Gonzalez-Juarrero

    Full Text Available Melioidosis is a disease in tropical and subtropical regions of the world that is caused by Burkholderia pseudomallei. In endemic regions the disease occurs primarily in humans and goats. In the present study, we used the goat as a model to dissect the polar lipids of B. pseudomallei to identify lipid molecules that could be used for adjuvants/vaccines or as diagnostic tools. We showed that the lipidome of B. pseudomallei and its fractions contain several polar lipids with the capacity to elicit different immune responses in goats, namely rhamnolipids and ornithine lipids which induced IFN-γ, whereas phospholipids and an undefined polar lipid induced strong IL-10 secretion in CD4(+ T cells. Autologous T cells co-cultured with caprine dendritic cells (cDCs and polar lipids of B. pseudomallei proliferated and up-regulated the expression of CD25 (IL-2 receptor molecules. Furthermore, we demonstrated that polar lipids were able to up-regulate CD1w2 antigen expression in cDCs derived from peripheral blood monocytes. Interestingly, the same polar lipids had only little effect on the expression of MHC class II DR antigens in the same caprine dendritic cells. Finally, antibody blocking of the CD1w2 molecules on cDCs resulted in decreased expression for IFN-γ by CD4(+ T cells. Altogether, these results showed that polar lipids of B. pseudomallei are recognized by the caprine immune system and that their recognition is primarily mediated by the CD1 antigen cluster.

  12. Acridone derivative 8a induces oxidative stress-mediated apoptosis in CCRF-CEM leukemia cells: application of metabolomics in mechanistic studies of antitumor agents.

    Directory of Open Access Journals (Sweden)

    Yini Wang

    Full Text Available A new acridone derivative, 2-aminoacetamido-10-(3, 5-dimethoxy-benzyl-9(10H-acridone hydrochloride (named 8a synthesized in our lab shows potent antitumor activity, but the mechanism of action remains unclear. Herein, we report the use of an UPLC/Q-TOF MS metabolomic approach to study the effects of three compounds with structures optimized step-by-step, 9(10H-acridone (A, 10-(3,5-dimethoxybenzyl-9(10H-acridone (I, and 8a, on CCRF-CEM leukemia cells and to shed new light on the probable antitumor mechanism of 8a. Acquired data were processed by principal component analysis (PCA and orthogonal partial least squares discriminant analysis (OPLS-DA to identify potential biomarkers. Comparing 8a-treated CCRF-CEM leukemia cells with vehicle control (DMSO, 23 distinct metabolites involved in five metabolic pathways were identified. Metabolites from glutathione (GSH and glycerophospholipid metabolism were investigated in detail, and results showed that GSH level and the reduced/oxidized glutathione (GSH/GSSG ratio were significantly decreased in 8a-treated cells, while L-cysteinyl-glycine (L-Cys-Gly and glutamate were greatly increased. In glycerophospholipid metabolism, cell membrane components phosphatidylcholines (PCs were decreased in 8a-treated cells, while the oxidative products lysophosphatidylcholines (LPCs were significantly increased. We further found that in 8a-treated cells, the reactive oxygen species (ROS and lipid peroxidation product malondialdehyde (MDA were notably increased, accompanied with decrease of mitochondrial transmembrane potential, release of cytochrome C and activation of caspase-3. Taken together our results suggest that the acridone derivative 8a induces oxidative stress-mediated apoptosis in CCRF-CEM leukemia cells. The UPLC/Q-TOF MS based metabolomic approach provides novel insights into the mechanistic studies of antitumor drugs from a point distinct from traditional biological investigations.

  13. Enhancement of antitumor effect of paclitaxel in combination with immunomodulatory Withania somnifera on benzo(a)pyrene induced experimental lung cancer.

    Science.gov (United States)

    Senthilnathan, Palaniyandi; Padmavathi, Radhakrishnan; Banu, Syed Mumtaz; Sakthisekaran, Dhanapal

    2006-02-25

    The current experimental work deals with the immunomodulatory studies on the extract of Withania somnifera (L.) Dunal root powder against benzo(a)pyrene induced lung cancer in male Swiss albino mice. In our previous study, we reported the antioxidant and anticarcinogenic effect of W. somnifera (L.) Dunal along with paclitaxel. Immune dysfunction has been found to be associated with cancer and chemotherapy. Benzo(a)pyrene induced cancer animals were treated with 400mg/kg bodyweight of W. somnifera (L.) Dunal extract for 30 days significantly alters the levels of immunocompetent cells, immune complexes and immunoglobulins. Based on the data, the carcinogen as well as the paclitaxel affects the immune system, the toxic side effects on the immune system is more reversible and more controllable by W. somnifera (L.) Dunal. These results concluded the immunomodulatory activity of W. somnifera (L.) Dunal extract, which is a known immunomodulator in indigenous medicine.

  14. Native and aspirin-triggered lipoxins control innate immunity by inducing proteasomal degradation of TRAF6

    OpenAIRE

    Machado, Fabiana S.; Esper, L?sia; Dias, Alexandra; Madan, Rajat; Gu, YuanYuan; Hildeman, David; Serhan, Charles N.; Karp, Christopher L.; Aliberti, J?lio

    2008-01-01

    Innate immune signaling is critical for the development of protective immunity. Such signaling is, perforce, tightly controlled. Lipoxins (LXs) are eicosanoid mediators that play key counterregulatory roles during infection. The molecular mechanisms underlying LX-mediated control of innate immune signaling are of interest. In this study, we show that LX and aspirin (ASA)-triggered LX (ATL) inhibit innate immune signaling by inducing suppressor of cytokine signaling (SOCS) 2–dependent ubiquiti...

  15. Sulfur Mustard Induces Immune Sensitization in Hairless Guinea Pigs

    Science.gov (United States)

    Mishra, Neerad C.; Rir-sima-ah, Jules; March, Thomas; Weber, Waylon; Benson, Janet; Jaramillo, Richard; Seagrave, Jean-Clare; Schultz, Gregory; Grotendorst, Gary; Sopori, Mohan

    2009-01-01

    Sulfur mustard (SM, bis-(2-chloroethyl) sulfide) is a well known chemical warfare agent that may cause long-term debilitating injury. Because of the ease of production and storage, it has a strong potential for chemical terrorism; however, the mechanism by which SM causes chronic tissue damage is essentially unknown. SM is a potent protein alkylating agent, and we tested the possibility that SM modifies cellular antigens, leading to an immunological response to “altered self” and a potential long-term injury. To that end, in this communication, we show that dermal exposure of euthymic hairless guinea pigs induced infiltration of both CD4+ and CD8+ T cells into the SM-exposed skin and strong upregulated expression of proinflammatory cytokines and chemokines (TNF-α, IFN-γ, and IL-8) in distal tissues such as the lung and the lymph nodes. Moreover, we present evidence for the first time that SM induces a specific delayed-type hypersensitivity response that is associated with splenomegaly, lymphadenopathy, and proliferation of cells in these tissues. These results clearly suggest that dermal exposure to SM leads to immune activation, infiltration of T cells into the SM-exposed skin, delayed-type hypersensitivity response, and molecular imprints of inflammation in tissues distal from the site of SM exposure. These immunological responses may contribute to the long-term sequelae of SM toxicity. PMID:19887117

  16. Unveiling Unexpected Immune Activities Induced by Your Pneumococcal Vaccine

    Directory of Open Access Journals (Sweden)

    Julia L. Hurwitz

    2016-03-01

    Full Text Available In modern-day vaccine design, a good pneumococcal capsular polysaccharide vaccine is measured by its ability to induce opsonic antibodies. These antibodies label bacteria for phagocytosis by neutrophils and thereby overcome the capsule’s barrier function. Doyle and Pirofski have raised a serious challenge to the current paradigm by describing anti-capsular antibodies that are highly protective but nonopsonic [C.R. Doyle and L. Pirofski, mBio 7(1:e02260-15, 2016, doi:10.1128/mBio.02260-15]. In fact, some functions are not related to neutrophils or phagocytosis at all. An increased awareness of these activities is critical not only for accurate comparisons of vaccine candidates but also for improvements in vaccination outcomes in settings of neutropenia. When vaccine developers select a single gatekeeper assay (e.g., an opsonophagocytic assay for bacteria or a neutralization assay for viruses, promising vaccine candidates may be missed. Doyle and Pirofski stress that multiple functions, not just one, should be investigated to enhance discovery of antibody mechanisms and to best assess vaccine-induced correlates of immune protection.

  17. Identification of hub genes related to silicone-induced immune response in rats

    OpenAIRE

    Huang, Xiaolu; Zhou, Yiwen; Liu, Wenhui; Li, Haizhou; Liang, Xiao; Jin, Rui; Du, Hengyu; He, Jizhou; Chai, Bangda; Duan, Ran; Li, Qingfeng

    2017-01-01

    Silicone implants are used widely in the field of plastic surgery and are used in a large population. However, their safety profile, especially the silicone-induced immune response, has been a major concern for plastic surgeons for decades. It has been hypothesized that there is a cause and effect relation between silicone and immunity, but this is controversial. The objective of the present study was to determine the hub genes and key pathways related to silicone implant–induced immune respo...

  18. Anti-Tumor Action, Clinical Biochemistry Profile and Phytochemical Constituents of a Pharmacologically Active Fraction of S. crispus in NMU-Induced Rat Mammary Tumour Model.

    Directory of Open Access Journals (Sweden)

    Nik Soriani Yaacob

    Full Text Available Cancer patients seek alternative remedies such as traditional medicinal plants for safe and effective treatment and help overcome the side effects of conventional therapy. Current knowledge indicates that extracts of Strobilanthes crispus of the Acanthaceae family exhibit potent anticancer properties in vitro and are non-toxic in vivo. S. crispus was also reported to be protective against chemical hepatocarcinogenesis. We previously showed that a bioactive fraction of S. crispus leaves also synergized with tamoxifen to cause apoptosis of human breast cancer cell lines without damaging non-malignant epithelial cells. The present study aimed to evaluate the antitumor effect of S. crispus dichloromethane fraction (F3 using N-methyl-N-Nitrosourea (NMU-induced rat mammary tumor model. Tumor regression was observed in 75% of the rats following 8-week oral administration of F3 with no secondary tumour formation and no signs of anemia or infection. However, no improvement in the liver and renal function profiles was observed. Major constituents of F3 were identified as lutein, 131-hydroxy-132-oxo-pheophytin a, campesterol, stigmasterol, β-sitosterol, pheophytin a and 132-hydroxy-pheophytin a. These compounds however, may not significantly contribute to the antitumor effect of F3.

  19. Immunizations, neonatal jaundice, and animal-induced injuries.

    Science.gov (United States)

    Morris, Shaine A; Bernstein, Henry H

    2004-08-01

    Published studies during the past year about three topics important to the pediatric clinician-- immunizations, neonatal jaundice, and animal-induced injuries-are concisely reviewed. Recent updates regarding vaccines including the questionable link with autism, implementation of universal influenza vaccination for young children, the efficacy of pneumococcal vaccine against invasive disease, and new information on pertussis, varicella, hepatitis A, hepatitis B, measles, and rotavirus vaccination are discussed. No association between measles/mumps/rubella vaccine or thimerosal-containing pertussis vaccine and autism is evident. Universal influenza vaccination for children 6 to 23 months of age will be recommended for the 2004-2005 flu season, and this implementation should reduce significant school absenteeism as well as complications seen last year including encephalopathy, seizures, respiratory failure, and pneumonia. Pneumococcal vaccine significantly reduces rates of invasive pneumococcal vaccine in healthy and HIV-infected children, although it does not appear to greatly affect otitis media rates. A reduction in post-vaccine febrile seizures appears to be present since the introduction of acellular pertussis vaccine. Multiple outbreaks in varicella have been reported since the introduction of the varicella vaccine, and a booster vaccination may be necessary in the future. Methods for detecting and preventing severe neonatal hyperbilirubinemia are reviewed, as well as anticipated recommendations from the American Academy of Pediatrics for the detection and management of hyperbilirubinemia. High bilirubin levels in preterm infants may result in hearing dysfunction and developmental impairment. The American Academy of Pediatrics has recommended a higher level of monitoring for newborn jaundice and treatment of hyperbilirubinemia in an effort to prevent kernicterus and sequelae from elevated bilirubin levels, including post-discharge follow-up appointment by day 3

  20. Pyruvate induces transient tumor hypoxia by enhancing mitochondrial oxygen consumption and potentiates the anti-tumor effect of a hypoxia-activated prodrug TH-302.

    Directory of Open Access Journals (Sweden)

    Yoichi Takakusagi

    Full Text Available BACKGROUND: TH-302 is a hypoxia-activated prodrug (HAP of bromo isophosphoramide mustard that is selectively activated within hypoxic regions in solid tumors. Our recent study showed that intravenously administered bolus pyruvate can transiently induce hypoxia in tumors. We investigated the mechanism underlying the induction of transient hypoxia and the combination use of pyruvate to potentiate the anti-tumor effect of TH-302. METHODOLOGY/RESULTS: The hypoxia-dependent cytotoxicity of TH-302 was evaluated by a viability assay in murine SCCVII and human HT29 cells. Modulation in cellular oxygen consumption and in vivo tumor oxygenation by the pyruvate treatment was monitored by extracellular flux analysis and electron paramagnetic resonance (EPR oxygen imaging, respectively. The enhancement of the anti-tumor effect of TH-302 by pyruvate treatment was evaluated by monitoring the growth suppression of the tumor xenografts inoculated subcutaneously in mice. TH-302 preferentially inhibited the growth of both SCCVII and HT29 cells under hypoxic conditions (0.1% O2, with minimal effect under aerobic conditions (21% O2. Basal oxygen consumption rates increased after the pyruvate treatment in SCCVII cells in a concentration-dependent manner, suggesting that pyruvate enhances the mitochondrial respiration to consume excess cellular oxygen. In vivo EPR oxygen imaging showed that the intravenous administration of pyruvate globally induced the transient hypoxia 30 min after the injection in SCCVII and HT29 tumors at the size of 500-1500 mm(3. Pretreatment of SCCVII tumor bearing mice with pyruvate 30 min prior to TH-302 administration, initiated with small tumors (∼ 550 mm(3, significantly delayed tumor growth. CONCLUSIONS/SIGNIFICANCE: Our in vitro and in vivo studies showed that pyruvate induces transient hypoxia by enhancing mitochondrial oxygen consumption in tumor cells. TH-302 therapy can be potentiated by pyruvate pretreatment if started at the

  1. Immunization

    Science.gov (United States)

    ... a lot worse. Some are even life-threatening. Immunization shots, or vaccinations, are essential. They protect against things like measles, ... B, polio, tetanus, diphtheria, and pertussis (whooping cough). Immunizations are important for adults as well as children. ...

  2. Oxazolone-induced contact hypersensitivity reduces lymphatic drainage but enhances the induction of adaptive immunity.

    Directory of Open Access Journals (Sweden)

    David Aebischer

    Full Text Available Contact hypersensitivity (CHS induced by topical application of haptens is a commonly used model to study dermal inflammatory responses in mice. Several recent studies have indicated that CHS-induced skin inflammation triggers lymphangiogenesis but may negatively impact the immune-function of lymphatic vessels, namely fluid drainage and dendritic cell (DC migration to draining lymph nodes (dLNs. On the other hand, haptens have been shown to exert immune-stimulatory activity by inducing DC maturation. In this study we investigated how the presence of pre-established CHS-induced skin inflammation affects the induction of adaptive immunity in dLNs. Using a mouse model of oxazolone-induced skin inflammation we observed that lymphatic drainage was reduced and DC migration from skin to dLNs was partially compromised. At the same time, a significantly stronger adaptive immune response towards ovalbumin (OVA was induced when immunization had occurred in CHS-inflamed skin as compared to uninflamed control skin. In fact, immunization with sterile OVA in CHS-inflamed skin evoked a delayed-type hypersensitivity (DTH response comparable to the one induced by conventional immunization with OVA and adjuvant in uninflamed skin. Striking phenotypic and functional differences were observed when comparing DCs from LNs draining uninflamed or CHS-inflamed skin. DCs from LNs draining CHS-inflamed skin expressed higher levels of co-stimulatory molecules and MHC molecules, produced higher levels of the interleukin-12/23 p40 subunit (IL-12/23-p40 and more potently induced T cell activation in vitro. Immunization experiments revealed that blockade of IL-12/23-p40 during the priming phase partially reverted the CHS-induced enhancement of the adaptive immune response. Collectively, our findings indicate that CHS-induced skin inflammation generates an overall immune-stimulatory milieu, which outweighs the potentially suppressive effect of reduced lymphatic vessel function.

  3. Increase in midgut microbiota load induces an apparent immune priming and increases tolerance to Bacillus thuringiensis.

    Science.gov (United States)

    Hernández-Martínez, Patricia; Naseri, Bahram; Navarro-Cerrillo, Gloria; Escriche, Baltasar; Ferré, Juan; Herrero, Salvador

    2010-10-01

    The insect immune system is comprised of both humoral and cellular components that are mobilized in response to parasitic or pathogenic infections. Activation of the immune response implies a considerable expenditure of energy and that is why insects rely on inducible pathways that are activated after coming into contact with the pathogenic agent. Known as immune priming, insects can prolong the activation of the immune response and transmit their immune status to the next generation. Starting from a laboratory colony of the lepidopteran Spodoptera exigua and using the lytic zone assay as a measure of the immune status, we selected for a sub-colony with high levels of immune activity in the absence of external challenging with bacteria. Immune-activated insect showed characteristics that are typical reported for immune primed insects, such as increased tolerance to pathogens (Bacillus thuringiensis in our case), fitness-cost associated to the immune status, and maternal transmission of the immune status. However, additional analysis revealed that the selection for the immune-activated insects was based on the selection of insects carrying a higher bacterial load in the midgut. Our results suggest that activation of the immune system in S. exigua may not only occur as consequence of the immune priming but also from an increase in midgut microbiota load. © 2010 Society for Applied Microbiology and Blackwell Publishing Ltd.

  4. The novel hypoxic cytotoxin, TX-2098 has antitumor effect in pancreatic cancer; possible mechanism through inhibiting VEGF and hypoxia inducible factor-1α targeted gene expression.

    Science.gov (United States)

    Miyake, Kotaro; Nishioka, Masanori; Imura, Satoru; Batmunkh, Erdenebulgan; Uto, Yoshihiro; Nagasawa, Hideko; Hori, Hitoshi; Shimada, Mitsuo

    2012-08-01

    Tumor hypoxia has been considered to be a potential therapeutic target, because hypoxia is a common feature of solid tumors and is associated with their malignant phenotype. In the present study, we investigated the antitumor effect of a novel hypoxic cytotoxin, 3-[2-hydroxyethyl(methyl)amino]-2-quinoxalinecarbonitrile 1,4-dioxide (TX-2098) in inhibiting the expression of hypoxia inducible factor-1α (HIF-1α), and consequently vascular endothelial cell growth factor (VEGF) expression in pancreatic cancer. The antitumor effects of TX-2098 under hypoxia were tested against various human pancreatic cancer cell lines using WST-8 assay. VEGF protein induced pancreatic cancer was determined on cell-free supernatant by ELISA. Moreover, nude mice bearing subcutaneously (s.c.) or orthotopically implanted human SUIT-2 were treated with TX-2098. Tumor volume, survival and expression of HIF-1 and associated molecules were evaluated in treatment versus control groups. In vitro, TX-2098 inhibited the proliferation of various pancreatic cancer cell lines. In s.c model, tumors from nude mice injected with pancreatic cancer cells and treated with TX-2098 showed significant reductions in volume (P<0.01 versus control). Quantitative real-time reverse transcription-PCR analysis revealed that TX-2098 significantly inhibited mRNA expression of the HIF-1 associated molecules, VEGF, glucose transporter 1 and Aldolase A (P<0.01 versus control). These treatments also prolong the survival in orthotopic models. These results suggest that the effect of TX-2098 in pancreatic cancer might be correlated with the expression of VEGF and HIF-1 targeted molecules. Copyright © 2012 Elsevier Inc. All rights reserved.

  5. [Advances in study on anti-tumor mechanism of andrographolide].

    Science.gov (United States)

    Qi, Cui-Ling; Wang, Li-Jing; Zhou, Xin-Lei

    2007-10-01

    In recent years, more and more attention was payed to the study of andrographolide. Andrographolide has the extensive pharmacological actions, such as anti-tumor, dephlogisticate and antibiosis and anti-virus. It was dected that andrographolide had the action of anti-tumor in gastric cancer, liver cancer, lung cancer and breast cancer. The anti-tumor mechanism of andrographolide was versatile, for instance, andrographolide can induce the apoptosis of cancer cell, inhibit the cell cycle, and increase the antitumor activity of lymphocyte. The following review was about the recent progress of study on the anti-tumor mechanism of andrographolide.

  6. Epidermal Langerhans' cell induction of immunity against an ultraviolet-induced skin tumour

    International Nuclear Information System (INIS)

    Cavanagh, L.L.; Sluyter, R.; Henderson, K.G.; Barnetson, R.St.C.; Halliday, G.M.

    1996-01-01

    Lanerghans' cells (LC) have been shown experimentally to induce immune response against many antigens; however, their role in the initiation of anti-tumour immunity has received little attention. This study examined the ability of murine epidermal LC to induce immunity to an ultraviolet radiation (UV)-induced skin tumour. Freshly prepared epidermal cells (EC) were cultured for 2 or 20 hr with granulocyte-macrophage colony-stimulating factor (GM-CSF), pulsed with an extract of the UV-13-1 tumour, then used to immunize naive syngeneic mice. Delayed type hypersensitivity (DTH) was elicited 10 days after immunization by injection of UV-13-1 tumour cells into the ear pinna, and measured 24 hr later. EC cultured with GM-CSF for 2 hr induced anti-tumour DTH, as did EC cultured for 20 hr without GM-CSF. Conversely, EC cultured for 2 hr without GM-CSF, or EC cultured for 20 hr with GM-CSF were unable to induce a DTH. Induction of immunity required active presentation of tumour antigens by Ia + EC and was tumour specific. Thus Ia + epidermal cells are capable of inducing anti-tumour immunity to UV-induced skin tumours, but only when they contact antigen in particular states of maturation. (author)

  7. [The humoral immune response in mice induced by recombinant Lactococcus lactis expressing HIV-1 gag].

    Science.gov (United States)

    Zhao, Xiaofei; Zhang, Cairong; Liu, Xiaojuan; Ma, Zhenghai

    2014-11-01

    To analyze the humoral immune response induced by recombinant Lactococcus lactis expressing HIV-1 gag in mice immunized orally, intranasally, subcutaneously or in the combined way of above three. Fifty BALB/c mice were randomly divided into 5 groups, 10 mice per group. The mice were immunized consecutively three times at two week intervals with 10(9) CFU of recombinant Lactococcus lactis expressing gag through oral, intranasal, subcutaneous administration or the mix of them. The mice that were immunized orally with Lactococcus lactis containing PMG36e served as a control group. The sera of mice were collected before primary immunization and 2 weeks after each immunization to detect the gag specific IgG by ELISA. Compared with the control group, the higher titer of serum gag specific IgG was detected in the four groups immunized with recombinant Lactococcus lactis expressing gag, and it was the highest in the mixed immunization group (PLactococcus lactis expressing gag can induce humoral immune response in mice by oral, intranasal, subcutaneous injection or the mix of them, and the mixed immunization can enhance the immune effects of Lactococcus lactis vector vaccine.

  8. Inducible viral receptor, A possible concept to induce viral protection in primitive immune animals

    Directory of Open Access Journals (Sweden)

    Pasharawipas Tirasak

    2011-06-01

    Full Text Available Abstract A pseudolysogen (PL is derived from the lysogenic Vibrio harveyi (VH which is infected with the VHS1 (Vibrio harveyi Siphoviridae-like 1 bacteriophage. The lysogenic Vibrio harveyi undergoes an unequivalent division of the extra-chromosomal VHS1 phage genome and its VH host chromosome and produces a true lysogen (TL and pseudolysogen (PL. The PL is tolerant to super-infection of VHS1, as is of the true lysogen (TL, but the PL does not contain the VHS1 phage genome while the TL does. However, the PL can become susceptible to VHS1 phage infection if the physiological state of the PL is changed. It is postulated that this is due to a phage receptor molecule which can be inducible to an on-and-off regulation influence by an alternating condition of the bacterial host cell. This characteristic of the PL leads to speculate that this phenomenon can also occur in high organisms with low immunity such as shrimp. This article proposes a hypothesis that the viral receptor molecule on the target cell can play a crucial role in which the invertebrate aquaculture animals can become tolerant to viral infection. A possible mechanism may be that the target cell disrupts the viral receptor molecule to prevent super infection. This concept can explain a mechanism for the prevention of viral infection in invertebrate animals which do not have acquired immunity in response to pathogens. It can guide us to develop a mechanism of immunity to viral infection in low-evolved-immune animals. Also, it can be an additional mechanism that exists in high immune organism, as in human for the prevention of viral infection

  9. 6-Nitro-2-(3-hydroxypropyl-1H-benz[de]isoquinoline-1,3-dione, a potent antitumor agent, induces cell cycle arrest and apoptosis

    Directory of Open Access Journals (Sweden)

    Singh Shashank K

    2010-12-01

    Full Text Available Abstract Background Anticancer activities of several substituted naphthalimides (1H-benz[de]isoquinoline-1,3-diones are well documented. Some of them have undergone Phase I-II clinical trials. Presently a series of ten N-(hydroxyalkyl naphthalimides (compounds 1a-j were evaluated as antitumor agents. Methods Compounds 1a-j were initially screened in MOLT-4, HL-60 and U-937 human tumor cell lines and results were compared with established clinical drugs. Cytotoxicities of compounds 1d and 1i were further evaluated in a battery of human tumor cell lines and in normal human peripheral blood mononuclear cells. Cell cycle analysis of compound 1i treated MOLT-4 cells was studied by flow cytometry. Its apoptosis inducing effect was carried out in MOLT-4 and HL-60 cells by flow cytometry using annexin V-FITC/PI double staining method. The activities of caspase-3 and caspase-6 in MOLT-4 cells following incubation with compound 1i were measured at different time intervals. Morphology of the MOLT-4 cells after treatment with 1i was examined under light microscope and transmission electron microscope. 3H-Thymidine and 3H-uridine incorporation in S-180 cells in vitro following treatment with 8 μM concentration of compounds 1d and 1i were studied. Results 6-Nitro-2-(3-hydroxypropyl-1H-benz[de]isoquinoline-1,3-dione (compound 1i, has exhibited maximum activity as it induced significant cytotoxicity in 8 out of 13 cell lines employed. Interestingly it did not show any cytotoxicity against human PBMC (IC50 value 273 μM. Cell cycle analysis of compound 1i treated MOLT-4 cells demonstrated rise in sub-G1 fraction and concomitant accumulation of cells in S and G2/M phases, indicating up-regulation of apoptosis along with mitotic arrest and/or delay in exit of daughter cells from mitotic cycle respectively. Its apoptosis inducing effect was confirmed in flow cytometric study in MOLT-4 and the action was mediated by activation of both caspase 3 and 6. Light and

  10. Immunotherapy and Immune Evasion in Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Thakur, Archana, E-mail: thakur@karmanos.org; Vaishampayan, Ulka [Department of Oncology, Wayne State University, Detroit, MI 48201 (United States); Lum, Lawrence G., E-mail: thakur@karmanos.org [Department of Oncology, Wayne State University, Detroit, MI 48201 (United States); Department of Medicine, Wayne State University, Detroit, MI 48201 (United States); Department of Immunology and Microbiology, Wayne State University, Detroit, MI 48201 (United States)

    2013-05-24

    Metastatic prostate cancer remains to this day a terminal disease. Prostatectomy and radiotherapy are effective for organ-confined diseases, but treatment for locally advanced and metastatic cancer remains challenging. Although advanced prostate cancers treated with androgen deprivation therapy achieves debulking of disease, responses are transient with subsequent development of castration-resistant and metastatic disease. Since prostate cancer is typically a slowly progressing disease, use of immune-based therapies offers an advantage to target advanced tumors and to induce antitumor immunity. This review will discuss the clinical merits of various vaccines and immunotherapies in castrate resistant prostate cancer and challenges to this evolving field of immune-based therapies.

  11. Immunometabolic Pathways in BCG-Induced Trained Immunity

    NARCIS (Netherlands)

    Arts, R.J.; Carvalho, A.; Rocca, C. La; Palma, C.; Rodrigues, F.; Silvestre, R.; Kleinnijenhuis, J.; Lachmandas, E.; Goncalves, L.G.; Belinha, A.; Cunha, C.; Oosting, M.; Joosten, L.A.; Matarese, G.; Crevel, R. van; Netea, M.G.

    2016-01-01

    The protective effects of the tuberculosis vaccine Bacillus Calmette-Guerin (BCG) on unrelated infections are thought to be mediated by long-term metabolic changes and chromatin remodeling through histone modifications in innate immune cells such as monocytes, a process termed trained immunity.

  12. Murine polyomavirus-VP1 virus-like particles immunize against some polyomavirus-induced tumours.

    Science.gov (United States)

    Franzén, Andrea Vlastos; Tegerstedt, Karin; Holländerova, Dana; Forstová, Jitka; Ramqvist, Torbjörn; Dalianis, Tina

    2005-01-01

    The ability of murine polyomavirus (MPyV)-VP1 virus-like particles (MPyV-VLPs) to immunize against MPyV tumour outgrowth was investigated. Non-immunized and mice immunized three times were challenged with MPyV or non-MPyV tumours and followed for tumour outgrowth. MPyV-VLP immunization abrogated outgrowth of some, but not all, tested MPyV tumours and delayed the outgrowth of a non-MPyV tumour to some extent. However, when mice were irradiated prior to tumour challenge to avoid an unspecific immune response, protection was MPyV-specific. In conclusion, VLP immunization for prevention of viral infection could also contribute to immune-protection against some tumours induced by the corresponding virus.

  13. Anti-tumor activities of luteolin and silibinin in glioblastoma cells: overexpression of miR-7-1-3p augmented luteolin and silibinin to inhibit autophagy and induce apoptosis in glioblastoma in vivo.

    Science.gov (United States)

    Chakrabarti, Mrinmay; Ray, Swapan K

    2016-03-01

    Glioblastoma is the deadliest brain tumor in humans. High systemic toxicity of conventional chemotherapies prompted the search for natural compounds for controlling glioblastoma. The natural flavonoids luteolin (LUT) and silibinin (SIL) have anti-tumor activities. LUT inhibits autophagy, cell proliferation, metastasis, and angiogenesis and induces apoptosis; while SIL activates caspase-8 cascades to induce apoptosis. However, synergistic anti-tumor effects of LUT and SIL in glioblastoma remain unknown. Overexpression of tumor suppressor microRNA (miR) could enhance the anti-tumor effects of LUT and SIL. Here, we showed that 20 µM LUT and 50 µM SIL worked synergistically for inhibiting growth of two different human glioblastoma U87MG (wild-type p53) and T98G (mutant p53) cell lines and natural combination therapy was more effective than conventional chemotherapy (10 µM BCNU or 100 µM TMZ). Combination of LUT and SIL caused inhibition of growth of glioblastoma cells due to induction of significant amounts of apoptosis and complete inhibition of invasion and migration. Further, combination of LUT and SIL inhibited rapamycin (RAPA)-induced autophagy, a survival mechanism, with suppression of PKCα and promotion of apoptosis through down regulation of iNOS and significant increase in expression of the tumor suppressor miR-7-1-3p in glioblastoma cells. Our in vivo studies confirmed that overexpression of miR-7-1-3p augmented anti-tumor activities of LUT and SIL in RAPA pre-treated both U87MG and T98G tumors. In conclusion, our results clearly demonstrated that overexpression of miR-7-1-3p augmented the anti-tumor activities of LUT and SIL to inhibit autophagy and induce apoptosis for controlling growth of different human glioblastomas in vivo.

  14. Gene-carried hepatoma targeting complex induced high gene transfection efficiency with low toxicity and significant antitumor activity

    Directory of Open Access Journals (Sweden)

    Zhao QQ

    2012-06-01

    was confirmed and the vector showed low cytotoxicity and strong targeting specificity to liver tumors in vitro. The in vivo study results showed that interleukin-12 delivered by the new gene vector CPT/DNA significantly enhanced the antitumor effect on ascites tumor-bearing imprinting control region mice as compared with polyethylenimine (25 kDa, CP, and other controls, which further demonstrate the targeting specificity of the new synthesized polymer.Conclusion: The synthesized CPT copolymer was proven to be an effective liver cancer-targeted vector for therapeutic gene delivery, which could be a potential candidate for targeted cancer gene therapy.Keywords: targeting, peptide, polyethylenimine, chitosan, antitumor

  15. Antitumor Activity of Portulaca Oleracea L. Polysaccharide on HeLa Cells Through Inducing TLR4/NF-κB Signaling.

    Science.gov (United States)

    Zhao, Rui; Zhang, Tao; Ma, Baoling; Li, Xing

    2017-01-01

    Abstarct We have previously shown that Portulaca oleracea L. polysaccharide (POL-P3b) possesses the ability to inhibit cervical cancer cell growth in vitro and in vivo. In this study, we explored how toll-like receptor 4 (TLR4) signaling correlated with the antitumor mechanism of POL-P3b. Western blotting was utilized to detect the expression of TLR4 and the downstream signaling pathway. The level of inflammatory mediator was quantified using enzyme-linked immunosorbent assay (ELISA) kits. The effects of POL-P3b on the proliferation and apoptosis in HeLa cells were determined by WST-8 assay and Hoechst 33342/propidium iodide (PI) assay. Our results demonstrated that lipopolysaccharide (LPS) binding to TLR4 on tumor cells could enhance HeLa cell proliferation and increase the expression of TLR4 and the downstream molecules. Treating HeLa cells with POL-P3b could decrease the proliferation of HeLa cells, and upregulate Bax level and downregulate Bcl-2 level in a concentration-dependent manner. In addition, POL-P3b inhibited the protein expression levels of TLR4, MyD88, TRAF6, Activator Protein-1 (AP-1) and nuclear factor-κB (NF-κB) subunit P65 in HeLa cells. Furthermore, POL-P3b also reduced the production of cytokine/chemokine. Taken together, the present work suggested the antitumor mechanism of POL-P3b by downregulating TLR4 downstream signaling pathway and inducing cell apoptosis. Our results may provide direct evidence to suggest that POL-P3b should be considered as a potent nutrient supplement for oncotherapy.

  16. Assessment of Cytokinin-Induced Immunity Through Quantification of Hyaloperonospora arabidopsidis Infection in Arabidopsis thaliana.

    Science.gov (United States)

    Watson, Ruth A; Argueso, Cristiana T

    2017-01-01

    Cytokinins have been shown to regulate plant immunity. Application of high levels of cytokinin to plants leads to decreased susceptibility to pathogens. In this chapter, we describe a fast and accurate protocol for assessment of cytokinin-induced immunity in Arabidopsis plants against an oomycete plant pathogen.

  17. Picornavirus-Induced Airway Mucosa Immune Profile in Asymptomatic Neonates

    DEFF Research Database (Denmark)

    Wolsk, Helene M.; Følsgaard, Nilofar V.; Birch, Sune

    2016-01-01

    , and regulatory immune paths. The association between immune mediator levels and viruses was tested by conventional statistics and partial least square discriminant analysis. Picornaviruses were detected in 58 neonates (10.2%) and other viruses in 10 (1.8%). A general up-regulation of immune mediators was found...... in the neonates with picornavirus (P partial least square discriminant analysis). The association was pronounced for type 1- and type 2-related markers and was unaffected by comprehensive confounder adjustment. Detection of picornavirus and bacteria was associated with an additive general up...

  18. Immunization of pregnant gilts with PRCV induces lactogenic immunity for protection of nursing piglets from challenge with TGEV.

    Science.gov (United States)

    Wesley, R D; Woods, R D

    1993-12-01

    The level of passive protection against transmissible gastroenteritis virus (TGEV) was evaluated by experimentally infecting 12 pregnant gilts with different doses of porcine respiratory coronavirus (PRCV) and challenging their litters at 4 days of age. An overall survival rate of 70% was found for piglets nursing the 12 PRCV-infected gilts, compared to a 16% survival rate for piglets of nine uninfected control gilts. Six of the PRCV-infected gilts had adequate levels of immunity to resist infection with TGEV following the challenge of their litters. These six completely immuned gilts also solidly protected their litters from TGEV as shown by a 96% piglet survival rate through weaning at 3 weeks of age. The results suggest that respiratory infection with PRCV induces a substantial degree of protective lactogenic immunity against TGEV.

  19. Effect of Scoparia dulcis on noise stress induced adaptive immunity and cytokine response in immunized Wistar rats.

    Science.gov (United States)

    Sundareswaran, Loganathan; Srinivasan, Sakthivel; Wankhar, Wankupar; Sheeladevi, Rathinasamy

    Noise acts as a stressor and is reported to have impact on individual health depending on nature, type, intensity and perception. Modern medicine has no effective drugs or cure to prevent its consequences. Being an environmental stressor noise cannot be avoided; instead minimizing its exposure or consuming anti-stressor and adaptogens from plants can be considered. The present study was carried out to evaluate the anti-stressor, adaptogen and immunostimulatory activity of Scoparia dulcis against noise-induced stress in Wistar rat models. Noise stress in rats was created by broadband white noise generator, 100 dB A/4 h daily/15 days and S. dulcis (200 mg/kg b.w.) was administered orally. 8 groups of rats were used consisting of 6 animals each; 4 groups for unimmunized and 4 groups for immunized. For immunization, sheep red blood cells (5 × 10 9  cells/ml) were injected intraperitoneally. Sub-acute noise exposed rats showed a significant increase in corticosterone and IL-4 levels in both immunized and unimmunized rats whereas lymphocytes, antibody titration, soluble immune complex, IL-4 showed a marked increase with a significant decrease in IL-2, TNF-α, IFN-γ cytokines only in unimmunized rats. Immunized noise exposed rats presented increased leukocyte migration index and decreased foot pad thickness, IL-2, TNF-α, IFN-γ with no changes in the lymphocytes. S. dulcis (SD) has normalized and prevented the noise induced changes in cell-mediated and humoral immunity and it could be the presence of anti-stressor and immuno stimulant activity of the plant. Copyright © 2016 Transdisciplinary University, Bangalore and World Ayurveda Foundation. Published by Elsevier B.V. All rights reserved.

  20. Immunity to transplantable nitrosourea-induced neurogenic tumors. III. Systemic adoptive transfer of immunity

    International Nuclear Information System (INIS)

    Shibuya, N.; Hochgeschwender, U.; Kida, Y.; Hochwald, G.M.; Thorbecke, G.J.; Cravioto, H.

    1984-01-01

    The effect of intravenously injected tumor immune spleen cells on growth of 3 X 10 5 gliosarcoma T 9 cells injected intradermally (ID) or intracerebrally (IC) into sublethally irradiated CDF rats was evaluated. Spleen cells from donor rats with sufficient immunity to reject 5 X 10 5 T 9 cells inhibited the growth of T 9 cells mixed with spleen cells in a ratio of 1:25 and injected ID, but could not act after intravenous transfer. However, donor rats which had rejected increasing T 9 challenge doses up to 1 X 10 7 cells produced immune spleen cells which, upon IV transfer, could inhibit growth of ID T 9 challenge but not of EB-679, an unrelated glioma, in recipient rats. Rejection of IC T 9 challenge was also obtained after IV transfer, in recipients of such ''hyperimmune'' spleen cells, but was less (60% maximum) than that noted after ID T 9 challenge (100% maximum). The removal of B cells from the transferred spleen cells did not affect the results, suggesting that the specific immunity was mediated by T cells. The authors conclude that the special immunological circumstances of tumors growing in the brain renders them less accessible to rejection by systemically transferred immune cells, but it is nevertheless possible to effect a significant incidence of rejection of syngeneic tumor growth in the brain by the intravenous transfer of hyperimmune spleen cells

  1. A role for immune responses against non-CS components in the cross-species protection induced by immunization with irradiated malaria sporozoites.

    Directory of Open Access Journals (Sweden)

    Marjorie Mauduit

    Full Text Available Immunization with irradiated Plasmodium sporozoites induces sterile immunity in rodents, monkeys and humans. The major surface component of the sporozoite the circumsporozoite protein (CS long considered as the antigen predominantly responsible for this immunity, thus remains the leading candidate antigen for vaccines targeting the parasite's pre-erythrocytic (PE stages. However, this role for CS was questioned when we recently showed that immunization with irradiated sporozoites (IrrSpz of a P. berghei line whose endogenous CS was replaced by that of P. falciparum still conferred sterile protection against challenge with wild type P. berghei sporozoites. In order to investigate the involvement of CS in the cross-species protection recently observed between the two rodent parasites P. berghei and P. yoelii, we adopted our gene replacement approach for the P. yoelii CS and exploited the ability to conduct reciprocal challenges. Overall, we found that immunization led to sterile immunity irrespective of the origin of the CS in the immunizing or challenge sporozoites. However, for some combinations, immune responses to CS contributed to the acquisition of protective immunity and were dependent on the immunizing IrrSpz dose. Nonetheless, when data from all the cross-species immunization/challenges were considered, the immune responses directed against non-CS parasite antigens shared by the two parasite species played a major role in the sterile protection induced by immunization with IrrSpz. This opens the perspective to develop a single vaccine formulation that could protect against multiple parasite species.

  2. Antitumor activity of intratracheal inhalation of temozolomide (TMZ) loaded into gold nanoparticles and/or liposomes against urethane-induced lung cancer in BALB/c mice.

    Science.gov (United States)

    Hamzawy, Mohamed A; Abo-Youssef, Amira M; Salem, Heba F; Mohammed, Sameh A

    2017-11-01

    The current study aimed to develop gold nanoparticles (GNPs) and liposome-embedded gold nanoparticles (LGNPs) as drug carriers for temozolomide (TMZ) and investigate the possible therapeutic effects of intratracheal inhalation of nanoformulation of TMZ-loaded gold nanoparticles (TGNPs) and liposome-embedded TGNPs (LTGNPs) against urethane-induced lung cancer in BALB/c mice. Physicochemical characters and zeta potential studies for gold nanoparticles (GNPs) and liposome-embedded gold nanoparticles (LGNPs) were performed. The current study was conducted by inducing lung cancer chemically via repeated exposure to urethane in BALB/C mice. GNPs and LGNPs were exhibited in uniform spherical shape with adequate dispersion stability. GNPs and LGNPs showed no significant changes in comparison to control group with high safety profile, while TGNPs and LTGNPs succeed to improve all biochemical data and histological patterns. GNPs and LGNPs are promising drug carriers and succeeded in the delivery of small and efficient dose of temozolomide in treatment lung cancer. Antitumor activity was pronounced in animal-treated LTGNPs, these effects may be due to synergistic effects resulted from combination of temozolomide and gold nanoparticles and liposomes that may improve the drug distribution and penetration.

  3. Tumor Cell Clone Expressing the Membrane-bound Form of IL-12p35 Subunit Stimulates Antitumor Immune Responses Dominated by CD8(+) T Cells.

    Science.gov (United States)

    Lim, Hoyong; Do, Seon Ah; Park, Sang Min; Kim, Young Sang

    2013-04-01

    IL-12 is a secretory heterodimeric cytokine composed of p35 and p40 subunits. IL-12 p35 and p40 subunits are sometimes produced as monomers or homodimers. IL-12 is also produced as a membrane-bound form in some cases. In this study, we hypothesized that the membrane-bound form of IL-12 subunits may function as a costimulatory signal for selective activation of TAA-specific CTL through direct priming without involving antigen presenting cells and helper T cells. MethA fibrosarcoma cells were transfected with expression vectors of membrane-bound form of IL-12p35 (mbIL-12p35) or IL-12p40 subunit (mbIL-12p40) and were selected under G418-containing medium. The tumor cell clones were analyzed for the expression of mbIL-12p35 or p40 subunit and for their stimulatory effects on macrophages. The responsible T-cell subpopulation for antitumor activity of mbIL-12p35 expressing tumor clone was also analyzed in T cell subset-depleted mice. Expression of transfected membrane-bound form of IL-12 subunits was stable during more than 3 months of in vitro culture, and the chimeric molecules were not released into culture supernatants. Neither the mbIL-12p35-expressing tumor clones nor mbIL-12p40-expressing tumor clones activated macrophages to secrete TNF-α. Growth of mbIL-12p35-expressing tumor clones was more accelerated in the CD8(+) T cell-depleted mice than in CD4(+) T cell-depleted or normal mice. These results suggest that CD8(+) T cells could be responsible for the rejection of mbIL-12p35-expressing tumor clone, which may bypass activation of antigen presenting cells and CD4(+) helper T cells.

  4. Tumor necrosis factor induces tumor promoting and anti-tumoral effects on pancreatic cancer via TNFR1.

    Directory of Open Access Journals (Sweden)

    Martin Chopra

    Full Text Available Multiple activities are ascribed to the cytokine tumor necrosis factor (TNF in health and disease. In particular, TNF was shown to affect carcinogenesis in multiple ways. This cytokine acts via the activation of two cell surface receptors, TNFR1, which is associated with inflammation, and TNFR2, which was shown to cause anti-inflammatory signaling. We assessed the effects of TNF and its two receptors on the progression of pancreatic cancer by in vivo bioluminescence imaging in a syngeneic orthotopic tumor mouse model with Panc02 cells. Mice deficient for TNFR1 were unable to spontaneously reject Panc02 tumors and furthermore displayed enhanced tumor progression. In contrast, a fraction of wild type (37.5%, TNF deficient (12.5%, and TNFR2 deficient mice (22.2% were able to fully reject the tumor within two weeks. Pancreatic tumors in TNFR1 deficient mice displayed increased vascular density, enhanced infiltration of CD4(+ T cells and CD4(+ forkhead box P3 (FoxP3(+ regulatory T cells (Treg but reduced numbers of CD8(+ T cells. These alterations were further accompanied by transcriptional upregulation of IL4. Thus, TNF and TNFR1 are required in pancreatic ductal carcinoma to ensure optimal CD8(+ T cell-mediated immunosurveillance and tumor rejection. Exogenous systemic administration of human TNF, however, which only interacts with murine TNFR1, accelerated tumor progression. This suggests that TNFR1 has basically the capability in the Panc02 model to trigger pro-and anti-tumoral effects but the spatiotemporal availability of TNF seems to determine finally the overall outcome.

  5. Acute psychological stress induces short-term variable immune response.

    Science.gov (United States)

    Breen, Michael S; Beliakova-Bethell, Nadejda; Mujica-Parodi, Lilianne R; Carlson, Joshua M; Ensign, Wayne Y; Woelk, Christopher H; Rana, Brinda K

    2016-03-01

    In spite of advances in understanding the cross-talk between the peripheral immune system and the brain, the molecular mechanisms underlying the rapid adaptation of the immune system to an acute psychological stressor remain largely unknown. Conventional approaches to classify molecular factors mediating these responses have targeted relatively few biological measurements or explored cross-sectional study designs, and therefore have restricted characterization of stress-immune interactions. This exploratory study analyzed transcriptional profiles and flow cytometric data of peripheral blood leukocytes with physiological (endocrine, autonomic) measurements collected throughout the sequence of events leading up to, during, and after short-term exposure to physical danger in humans. Immediate immunomodulation to acute psychological stress was defined as a short-term selective up-regulation of natural killer (NK) cell-associated cytotoxic and IL-12 mediated signaling genes that correlated with increased cortisol, catecholamines and NK cells into the periphery. In parallel, we observed down-regulation of innate immune toll-like receptor genes and genes of the MyD88-dependent signaling pathway. Correcting gene expression for an influx of NK cells revealed a molecular signature specific to the adrenal cortex. Subsequently, focusing analyses on discrete groups of coordinately expressed genes (modules) throughout the time-series revealed immune stress responses in modules associated to immune/defense response, response to wounding, cytokine production, TCR signaling and NK cell cytotoxicity which differed between males and females. These results offer a spring-board for future research towards improved treatment of stress-related disease including the impact of stress on cardiovascular and autoimmune disorders, and identifies an immune mechanism by which vulnerabilities to these diseases may be gender-specific. Copyright © 2015. Published by Elsevier Inc.

  6. Helminth Protein Vaccine Induced Follicular T Helper Cell for Enhancement of Humoral Immunity against Schistosoma japonicum

    Directory of Open Access Journals (Sweden)

    Jingyao Zhang

    2013-01-01

    Full Text Available Protein vaccines combined with adjuvants have been widely used to induce immune responses, especially the humoral immune response, against molecular targets including parasites. Follicular T helper (Tfh cells are the specialized providers of B-cell help, however, the induction of Tfh cells in protein vaccination has been rarely studied. Here, we report that the Schistosoma japonicum recombinant protein (SjGST-32 combined with tacrolimus (FK506 augmented the induction of Tfh cells, which expressed the canonical markers CXCR5, BCL6, and IL-21, and enhanced the humoral immune responses in BALB/c mice. Furthermore, the expression of IL-21R on germinal center (GC B cells and memory B cells increased in immunized mice, which indicated that IL-21 from the induced Tfh cells interacted with IL-21R for activation of B cells and maintenance of long-lived humoral immunity. Our results suggest that helminth protein vaccine combined with FK506 induces Tfh cell for stimulating humoral immune responses and inducing long-lived humoral immunity.

  7. Subversion of innate and adaptive immune activation induced by structurally modified lipopolysaccharide from Salmonella typhimurium.

    Science.gov (United States)

    Pastelin-Palacios, Rodolfo; Gil-Cruz, Cristina; Pérez-Shibayama, Christian I; Moreno-Eutimio, Mario A; Cervantes-Barragán, Luisa; Arriaga-Pizano, Lourdes; Ludewig, Burkhard; Cunningham, Adam F; García-Zepeda, Eduardo A; Becker, Ingeborg; Alpuche-Aranda, Celia; Bonifaz, Laura; Gunn, John S; Isibasi, Armando; López-Macías, Constantino

    2011-08-01

    Salmonella are successful pathogens that infect millions of people every year. During infection, Salmonella typhimurium changes the structure of its lipopolysaccharide (LPS) in response to the host environment, rendering bacteria resistant to cationic peptide lysis in vitro. However, the role of these structural changes in LPS as in vivo virulence factors and their effects on immune responses and the generation of immunity are largely unknown. We report that modified LPS are less efficient than wild-type LPS at inducing pro-inflammatory responses. The impact of this LPS-mediated subversion of innate immune responses was demonstrated by increased mortality in mice infected with a non-lethal dose of an attenuated S. typhimurium strain mixed with the modified LPS moieties. Up-regulation of co-stimulatory molecules on antigen-presenting cells and CD4(+) T-cell activation were affected by these modified LPS. Strains of S. typhimurium carrying structurally modified LPS are markedly less efficient at inducing specific antibody responses. Immunization with modified LPS moiety preparations combined with experimental antigens, induced an impaired Toll-like receptor 4-mediated adjuvant effect. Strains of S. typhimurium carrying structurally modified LPS are markedly less efficient at inducing immunity against challenge with virulent S. typhimurium. Hence, changes in S. typhimurium LPS structure impact not only on innate immune responses but also on both humoral and cellular adaptive immune responses. © 2011 The Authors. Immunology © 2011 Blackwell Publishing Ltd.

  8. BAY 87-2243, a highly potent and selective inhibitor of hypoxia-induced gene activation has antitumor activities by inhibition of mitochondrial complex I

    International Nuclear Information System (INIS)

    Ellinghaus, Peter; Heisler, Iring; Unterschemmann, Kerstin; Haerter, Michael; Beck, Hartmut; Greschat, Susanne; Ehrmann, Alexander; Summer, Holger; Flamme, Ingo; Oehme, Felix; Thierauch, Karlheinz; Michels, Martin; Hess-Stumpp, Holger; Ziegelbauer, Karl

    2013-01-01

    The activation of the transcription factor hypoxia-inducible factor-1 (HIF-1) plays an essential role in tumor development, tumor progression, and resistance to chemo- and radiotherapy. In order to identify compounds targeting the HIF pathway, a small molecule library was screened using a luciferase-driven HIF-1 reporter cell line under hypoxia. The high-throughput screening led to the identification of a class of aminoalkyl-substituted compounds that inhibited hypoxia-induced HIF-1 target gene expression in human lung cancer cell lines at low nanomolar concentrations. Lead structure BAY 87-2243 was found to inhibit HIF-1α and HIF-2α protein accumulation under hypoxic conditions in non-small cell lung cancer (NSCLC) cell line H460 but had no effect on HIF-1α protein levels induced by the hypoxia mimetics desferrioxamine or cobalt chloride. BAY 87-2243 had no effect on HIF target gene expression levels in RCC4 cells lacking Von Hippel–Lindau (VHL) activity nor did the compound affect the activity of HIF prolyl hydroxylase-2. Antitumor activity of BAY 87-2243, suppression of HIF-1α protein levels, and reduction of HIF-1 target gene expression in vivo were demonstrated in a H460 xenograft model. BAY 87-2243 did not inhibit cell proliferation under standard conditions. However under glucose depletion, a condition favoring mitochondrial ATP generation as energy source, BAY 87-2243 inhibited cell proliferation in the nanomolar range. Further experiments revealed that BAY 87-2243 inhibits mitochondrial complex I activity but has no effect on complex III activity. Interference with mitochondrial function to reduce hypoxia-induced HIF-1 activity in tumors might be an interesting therapeutic approach to overcome chemo- and radiotherapy-resistance of hypoxic tumors

  9. Chloroquine upregulates TRAIL/TRAILR2 expression and potentiates doxorubicin anti-tumor activity in thioacetamide-induced hepatocellular carcinoma model.

    Science.gov (United States)

    Helmy, Sahar A; El-Mesery, Mohamed; El-Karef, Amro; Eissa, Laila A; El Gayar, Amal M

    2018-01-05

    Impaired apoptosis and systemic toxicity of chemotherapeutic drugs make cancer treatment suboptimal. Thus, there is urgency for drug repurposing which facilitates discovery of safe and effective combination therapy. This study aimed to evaluate chloroquine's (CQ) ability to trigger TRAIL/TRAILR2 apoptotic pathway in thioacetamide (TAA)-induced hepatocellular carcinoma (HCC) either alone or in combination with doxorubicin (DOX). Moreover, its ability to attenuate DOX-induced cardiotoxicity was investigated. TAA was injected in male Sprague Dawely rats (200 mg/kg; ip; 2 times/week) for 16 weeks. After the 16th week, rats were further divided into different groups (n = 10) and treated for 7 weeks. CQ group (received CQ 25 mg/kg/day; orally), DOX group (received DOX 1 mg/kg; ip; 2 times/week) and CQ/DOX group. Liver function biomarkers, AFP, hepatic levels of MDA and GSH, serum CK-MB and LDH enzymes activity were measured. Quantitative, Real-Time PCR was used to measure TRAIL, TRAILR2, caspase-8, caspase-9, caspase-3, BCL-2 and TGF-β1 genes expression levels. Necroinflammation and fibrosis were scored by histopathological examination. CQ improved liver functions, reduced AFP level and attenuated HCC progression. CQ induced apoptosis via upregulation of TRAIL/TRAILR2, caspase-8, caspase-3 and caspase-8 genes and downregulation of BCL-2 gene. Moreover, CQ/DOX showed marked decrease in hepatic MDA level, serum CK-MB, LDH enzymes activity, as well as marked increase in hepatic GSH level. In conclusion, this work assess the in vivo efficacy of CQ/DOX combination therapy in this HCC model that not only has enhanced anti-tumor activity but it also protects against DOX-induced cardiotoxicity. Nevertheless, more studies should be performed to illustrate the molecular mechanism of CQ's cardioprotective effect. Copyright © 2017. Published by Elsevier B.V.

  10. In vitro and in vivo studies on antitumor effects of gossypol on human stomach adenocarcinoma (AGS) cell line and MNNG induced experimental gastric cancer

    International Nuclear Information System (INIS)

    Gunassekaran, G.R.; Kalpana Deepa Priya, D.; Gayathri, R.; Sakthisekaran, D.

    2011-01-01

    Highlights: → Gossypol is a well known polyphenolic compound used for anticancer studies but we are the first to report that gossypol has antitumor effect on MNNG induced gastric cancer in experimental animal models. → Our study shows that gossypol inhibits the proliferation of AGS (human gastric adenocarcinoma) cell line. → In animal models, gossypol extends the survival of cancer bearing animals and also protects the cells from carcinogenic effect. → So we suggest that gossypol would be a potential chemotherapeutic and chemopreventive agent for gastric cancer. -- Abstract: The present study has evaluated the chemopreventive effects of gossypol on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced gastric carcinogenesis and on human gastric adenocarcinoma (AGS) cell line. Gossypol, C 30 H 30 O 8 , is a polyphenolic compound that has anti proliferative effect and induces apoptosis in various cancer cells. The aim of this work was to delineate in vivo and in vitro anti-initiating mechanisms of orally administered gossypol in target (stomach) tissues and in human gastric adenocarcinoma (AGS) cell line. In vitro results prove that gossypol has potent cytotoxic effect and inhibit the proliferation of adenocarcinoma (AGS) cell line. In vivo results prove gossypol to be successful in prolonging the survival of MNNG induced cancer bearing animals and in delaying the onset of tumor in animals administrated with gossypol and MNNG simultaneously. Examination of the target (stomach) tissues in sacrificed experimental animals shows that administration of gossypol significantly reduces the level of tumor marker enzyme (carcino embryonic antigen) and pepsin. The level of Nucleic acid contents (DNA and RNA) significantly reduces, and the membrane damage of glycoprotein subsides, in the target tissues of cancer bearing animals, with the administration of gossypol. These data suggest that gossypol may create a beneficial effect in patients with gastric cancer.

  11. The novel hypoxic cytotoxin, TX-2098 has antitumor effect in pancreatic cancer; possible mechanism through inhibiting VEGF and hypoxia inducible factor-1{alpha} targeted gene expression

    Energy Technology Data Exchange (ETDEWEB)

    Miyake, Kotaro, E-mail: hif.panc@gmail.com [Department of Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503 (Japan); Nishioka, Masanori; Imura, Satoru; Batmunkh, Erdenebulgan [Department of Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503 (Japan); Uto, Yoshihiro [Department of Biological Science and Technology, Institute of Socio Technosciences, The University of Tokushima Graduate School, Tokushima 770-8503 (Japan); Nagasawa, Hideko [Laboratory of Pharmaceutical and Medicinal Chemistry, Gifu Pharmaceutical University, Gifu 501-1196 (Japan); Hori, Hitoshi [Department of Biological Science and Technology, Institute of Socio Technosciences, The University of Tokushima Graduate School, Tokushima 770-8503 (Japan); Shimada, Mitsuo [Department of Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503 (Japan)

    2012-08-01

    Tumor hypoxia has been considered to be a potential therapeutic target, because hypoxia is a common feature of solid tumors and is associated with their malignant phenotype. In the present study, we investigated the antitumor effect of a novel hypoxic cytotoxin, 3-[2-hydroxyethyl(methyl)amino]-2-quinoxalinecarbonitrile 1,4-dioxide (TX-2098) in inhibiting the expression of hypoxia inducible factor-1{alpha} (HIF-1{alpha}), and consequently vascular endothelial cell growth factor (VEGF) expression in pancreatic cancer. The antitumor effects of TX-2098 under hypoxia were tested against various human pancreatic cancer cell lines using WST-8 assay. VEGF protein induced pancreatic cancer was determined on cell-free supernatant by ELISA. Moreover, nude mice bearing subcutaneously (s.c.) or orthotopically implanted human SUIT-2 were treated with TX-2098. Tumor volume, survival and expression of HIF-1 and associated molecules were evaluated in treatment versus control groups. In vitro, TX-2098 inhibited the proliferation of various pancreatic cancer cell lines. In s.c model, tumors from nude mice injected with pancreatic cancer cells and treated with TX-2098 showed significant reductions in volume (P < 0.01 versus control). Quantitative real-time reverse transcription-PCR analysis revealed that TX-2098 significantly inhibited mRNA expression of the HIF-1 associated molecules, VEGF, glucose transporter 1 and Aldolase A (P < 0.01 versus control). These treatments also prolong the survival in orthotopic models. These results suggest that the effect of TX-2098 in pancreatic cancer might be correlated with the expression of VEGF and HIF-1 targeted molecules. -- Highlights: Black-Right-Pointing-Pointer We designed and synthesized novel hypoxic cytoxin, TX-2098. Black-Right-Pointing-Pointer TX-2098 inhibited the proliferation of human pancreatic cancer cells than TPZ. Black-Right-Pointing-Pointer TX-2098 reduced VEGF protein level than TPZ. Black-Right-Pointing-Pointer TX-2098

  12. Immunity and Tolerance Induced by Intestinal Mucosal Dendritic Cells

    Directory of Open Access Journals (Sweden)

    Julio Aliberti

    2016-01-01

    Full Text Available Dendritic cells present in the digestive tract are constantly exposed to environmental antigens, commensal flora, and invading pathogens. Under steady-state conditions, these cells have high tolerogenic potential, triggering differentiation of regulatory T cells to protect the host from unwanted proinflammatory immune responses to innocuous antigens or commensals. On the other hand, these cells must discriminate between commensal flora and invading pathogens and mount powerful immune response against pathogens. A potential result of unbalanced tolerogenic versus proinflammatory responses mediated by dendritic cells is associated with chronic inflammatory conditions, such as Crohn’s disease, ulcerative colitis, food allergies, and celiac disease. Herein, we review the dendritic cell population involved in mediating tolerance and immunity in mucosal surfaces, the progress in unveiling their development in vivo, and factors that can influence their functions.

  13. Sperm storage induces an immunity cost in ants

    DEFF Research Database (Denmark)

    Baer, Boris; Armitage, Sophie A O; Boomsma, Jacobus J

    2006-01-01

    Ant queens are among the most long-lived insects known. They mate early in adult life and maintain millions of viable sperm in their sperm storage organ until they die many years later. Because they never re-mate, the reproductive success of queens is ultimately sperm-limited, but it is not known...... what selective forces determine the upper limit to sperm storage. Here we show that sperm storage carries a significant cost of reduced immunity during colony founding. Newly mated queens of the leaf-cutting ant Atta colombica upregulate their immune response shortly after completing their nest burrow......, probably as an adaptive response to a greater exposure to pathogens in the absence of grooming workers. However, the immune response nine days after colony founding is negatively correlated with the amount of sperm in the sperm storage organ, indicating that short-term survival is traded off against long...

  14. DIF-1, an anti-tumor substance found in Dictyostelium discoideum, inhibits progesterone-induced oocyte maturation in Xenopus laevis.

    Science.gov (United States)

    Kubohara, Yuzuru; Hanaoka, Yoichi; Akaishi, Emi; Kobayashi, Hisae; Maeda, Mineko; Hosaka, Kohei

    2003-01-24

    Differentiation-inducing factor-1 (DIF-1; 1-(3,5-dichloro-2,6-dihydroxy-4-methoxyphenyl)hexan-1-one) is a putative morphogen that induces stalk-cell formation in the cellular slime mold Dictyostelium discoideum. DIF-1 has previously been shown to suppress cell growth in mammalian cells. In this study, we examined the effects of DIF-1 on the progesterone-induced germinal vesicle breakdown in Xenopus laevis, which is thought to be mediated by a decrease in intracellular cAMP and the subsequent activation of mitogen-activated protein kinase (MAPK) and maturation-promoting factor, a complex of cdc2 and cyclin B, which regulates germinal vesicle breakdown. DIF-1 at 10-40 microM inhibited progesterone-induced germinal vesicle breakdown in de-folliculated oocytes in a dose-dependent manner. Progesterone-induced cdc2 activation, MAPK activation, and c-Mos accumulation were inhibited by DIF-1. Furthermore, DIF-1 was found to inhibit the progesterone-induced cAMP decrease in the oocytes. These results indicate that DIF-1 inhibits progesterone-induced germinal vesicle breakdown possibly by blocking the progesterone-induced decrease in [cAMP](i) and the subsequent events in Xenopus oocytes.

  15. CD40-independent natural killer-cell help promotes dendritic cell vaccine-induced T-cell immunity against endogenous B-cell lymphoma.

    Science.gov (United States)

    Hömberg, Nadine; Adam, Christian; Riedel, Tanja; Brenner, Christoph; Flatley, Andrew; Röcken, Martin; Mocikat, Ralph

    2014-12-15

    It is well established that an interplay between natural killer (NK) cells and dendritic cells (DCs) gives rise to their reciprocal activation and provides a Th1-biased cytokine milieu that fosters antitumor T-cell responses. Ex vivo-differentiated DCs transferred into mice strongly stimulate endogenous NK cells to produce interferon (IFN)-γ and initiate a cascade that eventually leads to cytotoxic T-lymphocyte responses. We show that the ability of exogenous DCs to trigger this pathway obviates CD40 signaling and CD4(+) T-cell help and depends on a preceding maturation step. Importantly, this mechanism was also effective in endogenously arising tumors where IFN-γ production is compromised in contrast to transplantable tumors. In c-myc-transgenic mice developing spontaneous lymphomas, injection of unpulsed DCs caused NK-cell activation and induced CD8(+) T cells capable of recognizing the lymphoma cells. Animals treated with unpulsed DCs showed a survival benefit compared to untreated myc mice. Hence, tumor immunity induced by DC-based vaccines not only depends on specific antigens loaded on the DCs. Rather, DC vaccines generate broader immune responses, because endogenous DCs presenting tumor antigens may also become stimulated by NK cells that were activated by exogenous DCs. Thus, the DC/NK-cell/cytotoxic T lymphocyte axis may commonly have relevance for DC-based vaccination protocols in clinical settings. © 2014 UICC.

  16. Sunitinib indirectly enhanced anti-tumor cytotoxicity of cytokine-induced killer cells and CD3⁺CD56⁺ subset through the co-culturing dendritic cells.

    Directory of Open Access Journals (Sweden)

    Adisak Wongkajornsilp

    Full Text Available Cytokine-induced killer (CIK cells have reached clinical trials for leukemia and solid tumors. Their anti-tumor cytotoxicity had earlier been shown to be intensified after the co-culture with dendritic cells (DCs. We observed markedly enhanced anti-tumor cytotoxicity activity of CIK cells after the co-culture with sunitinib-pretreated DCs over that of untreated DCs. This cytotoxicity was reliant upon DC modulation by sunitinib because the direct exposure of CIK cells to sunitinib had no significant effect. Sunitinib promoted Th1-inducing and pro-inflammatory phenotypes (IL-12, IFN-γ and IL-6 in DCs at the expense of Th2 inducing phenotype (IL-13 and regulatory phenotype (PD-L1, IDO. Sunitinib-treated DCs subsequently induced the upregulation of Th1 phenotypic markers (IFN-γ and T-bet and the downregulation of the Th2 signature (GATA-3 and the Th17 marker (RORC on the CD3⁺CD56⁺ subset of CIK cells. It concluded that sunitinib-pretreated DCs drove the CD3⁺CD56⁺ subset toward Th1 phenotype with increased anti-tumor cytotoxicity.

  17. Nano-Pulse Stimulation induces immunogenic cell death in human papillomavirus-transformed tumors and initiates an adaptive immune response.

    Directory of Open Access Journals (Sweden)

    Joseph G Skeate

    Full Text Available Nano-Pulse Stimulation (NPS is a non-thermal pulsed electric field modality that has been shown to have cancer therapeutic effects. Here we applied NPS treatment to the human papillomavirus type 16 (HPV 16-transformed C3.43 mouse tumor cell model and showed that it is effective at eliminating primary tumors through the induction of immunogenic cell death while subsequently increasing the number of tumor-infiltrating lymphocytes within the tumor microenvironment. In vitro NPS treatment of C3.43 cells resulted in a doubling of activated caspase 3/7 along with the translocation of phosphatidylserine (PS to the outer leaflet of the plasma membrane, indicating programmed cell death activity. Tumor-bearing mice receiving standard NPS treatment showed an initial decrease in tumor volume followed by clearing of tumors in most mice, and a significant increase in overall survival. Intra-tumor analysis of mice that were unable to clear tumors showed an inverse correlation between the number of tumor infiltrating lymphocytes and the size of the tumor. Approximately half of the mice that cleared established tumors were protected against tumor re-challenge on the opposite flank. Selective depletion of CD8+ T cells eliminated this protection, suggesting that NPS treatment induces an adaptive immune response generating CD8+ T cells that recognize tumor antigen(s associated with the C3.43 tumor model. This method may be utilized in the future to not only ablate primary tumors, but also to induce an anti-tumor response driven by effector CD8+ T cells capable of protecting individuals from disease recurrence.

  18. MiR-15a/16 deficiency enhances anti-tumor immunity of glioma-infiltrating CD8+ T cells through targeting mTOR.

    Science.gov (United States)

    Yang, Jiao; Liu, Ronghua; Deng, Yuting; Qian, Jiawen; Lu, Zhou; Wang, Yuedi; Zhang, Dan; Luo, Feifei; Chu, Yiwei

    2017-11-15

    MiR-15a/16, a miRNA cluster located at chromosome 13q14, has been reported to act as an immune regulator in inflammatory disorders besides its aberrant expression in cancers. However, little is known about its regulation in tumor-infiltrating immune cells. In our study, using an orthotropic GL261 mouse glioma model, we found that miR-15a/16 deficiency in host inhibited tumor growth and prolonged mice survival, which might be associated with the accumulation of tumor-infiltrating CD8+ T cells. More importantly, tumor-infiltrating CD8+ T cells without miR-15a/16 showed lower expression of PD-1, Tim-3 and LAG-3, and stronger secretion of IFN-γ, IL-2 and TNF-α than WT tumor-infiltrating CD8+ T cells. Also, our in vitro experiments further confirmed that miR-15a/16 -/- CD8+ T displayed higher active phenotypes, more cytokines secretion and faster expansion, compared to WT CD8+ T cells. Mechanismly, mTOR was identified as a target gene of miR-15a/16 to negatively regulate the activation of CD8+ T cells. Taken together, these data suggest that miR-15a/16 deficiency resists the exhaustion and maintains the activation of glioma-infiltrating CD8+ T cells to alleviate glioma progression via targeting mTOR. Our findings provide evidence for the potential immunotherapy through targeting miR-15a/16 in tumor-infiltrating immune cells. © 2017 UICC.

  19. Behavioral effects induced by antitumor cleronade diterpenes from Casearia sylvestris and in silico interactions with neuron receptors.

    Science.gov (United States)

    de Araújo, Éverton José Ferreira; de Almeida, Antônia Amanda Cardoso; Silva, Oskar Almeida; da Costa, Iwyson Henrique Fernandes; Rezende-Júnior, Luis Mário; Lima, Francisco das Chagas Alves; Cavalheiro, Alberto José; Pessoa, Cláudia; de Moraes, Manoel Odorico; Ferreira, Paulo Michel Pinheiro

    2017-02-23

    Casearia sylvestris is a medicinal plant traditionally used to treat snakebites, wounds, inflammation and gastric ulcers and scientific supports for have demonstrated its antitumor, antihyperlipidemic and antiparasitic properties. To assess the effects of a fraction with casearins (FC) on adult mice using classical experimental models of animal behavior and theoretical calculations to verify the interaction of Casearin X (Cas X) with neuron receptors. Animals divided in 6 groups (n=9/group) were intraperitoneally treated with vehicle (DMSO 4%), FC (2.5, 5, 10 and 25mg/kg/day) and diazepam (2mg/kg) for 7 days. Thirty minutes after the last dose of treatment, acute toxicity and behavioral experiments were performed. The highest dose of FC (25mg/kg/day) caused diarrhea, weight loss and death of one animal. Elevated plus maze test showed that lower doses [2.5mg/kg/day (36.4±5.1s) and 5mg/kg/day (43.9±6.2s)] increased the time spent in open arms (TSOA). Open field test revealed reduction in the number of crossings (54.9%, 51.1%, 48% and 67.7% for 2.5, 5, 10 and 25mg/kg/day, respectively) in all doses of FC studied and decrease of rearings at 25mg/kg/day (p<0.05). Computational calculations showed that the inhibition constant (Ki) for the Cas X-D 1 complex is up to 1000-fold more favourable than the Cas X-GABA A complex. All ∆G° values obtained for Cas X-D 1 complexes were more negative than those seen with Cas X-GABA A complexes. Findings indicate a probable anxiolytic action of the FC since it reduces the number of crossings and rearings and prolonged the time spent in open arms, without sedative and myorelaxant effects, probably due to the interaction of Cas X with dopaminergic system. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

  20. Perturbation of gut bacteria induces a coordinated cellular immune response in the purple sea urchin larva.

    Science.gov (United States)

    Ch Ho, Eric; Buckley, Katherine M; Schrankel, Catherine S; Schuh, Nicholas W; Hibino, Taku; Solek, Cynthia M; Bae, Koeun; Wang, Guizhi; Rast, Jonathan P

    2016-10-01

    The purple sea urchin (Strongylocentrotus purpuratus) genome sequence contains a complex repertoire of genes encoding innate immune recognition proteins and homologs of important vertebrate immune regulatory factors. To characterize how this immune system is deployed within an experimentally tractable, intact animal, we investigate the immune capability of the larval stage. Sea urchin embryos and larvae are morphologically simple and transparent, providing an organism-wide model to view immune response at cellular resolution. Here we present evidence for immune function in five mesenchymal cell types based on morphology, behavior and gene expression. Two cell types are phagocytic; the others interact at sites of microbial detection or injury. We characterize immune-associated gene markers for three cell types, including a perforin-like molecule, a scavenger receptor, a complement-like thioester-containing protein and the echinoderm-specific immune response factor 185/333. We elicit larval immune responses by (1) bacterial injection into the blastocoel and (2) seawater exposure to the marine bacterium Vibrio diazotrophicus to perturb immune state in the gut. Exposure at the epithelium induces a strong response in which pigment cells (one type of immune cell) migrate from the ectoderm to interact with the gut epithelium. Bacteria that accumulate in the gut later invade the blastocoel, where they are cleared by phagocytic and granular immune cells. The complexity of this coordinated, dynamic inflammatory program within the simple larval morphology provides a system in which to characterize processes that direct both aspects of the echinoderm-specific immune response as well as those that are shared with other deuterostomes, including vertebrates.

  1. Perturbation of gut bacteria induces a coordinated cellular immune response in the purple sea urchin larva

    Science.gov (United States)

    CH Ho, Eric; Buckley, Katherine M; Schrankel, Catherine S; Schuh, Nicholas W; Hibino, Taku; Solek, Cynthia M; Bae, Koeun; Wang, Guizhi; Rast, Jonathan P

    2016-01-01

    The purple sea urchin (Strongylocentrotus purpuratus) genome sequence contains a complex repertoire of genes encoding innate immune recognition proteins and homologs of important vertebrate immune regulatory factors. To characterize how this immune system is deployed within an experimentally tractable, intact animal, we investigate the immune capability of the larval stage. Sea urchin embryos and larvae are morphologically simple and transparent, providing an organism-wide model to view immune response at cellular resolution. Here we present evidence for immune function in five mesenchymal cell types based on morphology, behavior and gene expression. Two cell types are phagocytic; the others interact at sites of microbial detection or injury. We characterize immune-associated gene markers for three cell types, including a perforin-like molecule, a scavenger receptor, a complement-like thioester-containing protein and the echinoderm-specific immune response factor 185/333. We elicit larval immune responses by (1) bacterial injection into the blastocoel and (2) seawater exposure to the marine bacterium Vibrio diazotrophicus to perturb immune state in the gut. Exposure at the epithelium induces a strong response in which pigment cells (one type of immune cell) migrate from the ectoderm to interact with the gut epithelium. Bacteria that accumulate in the gut later invade the blastocoel, where they are cleared by phagocytic and granular immune cells. The complexity of this coordinated, dynamic inflammatory program within the simple larval morphology provides a system in which to characterize processes that direct both aspects of the echinoderm-specific immune response as well as those that are shared with other deuterostomes, including vertebrates. PMID:27192936

  2. Programmed death ligand 2 in cancer-induced immune suppression

    NARCIS (Netherlands)

    Rozali, Esdy N.; Hato, Stanleyson V.; Robinson, Bruce W.; Lake, Richard A.; Lesterhuis, W. Joost

    2012-01-01

    Inhibitory molecules of the B7/CD28 family play a key role in the induction of immune tolerance in the tumor microenvironment. The programmed death-1 receptor (PD-1), with its ligands PD-L1 and PD-L2, constitutes an important member of these inhibitory pathways. The relevance of the PD-1/PD-L1

  3. A mechanism for trauma induced muscle wasting and immune dysfunction

    Science.gov (United States)

    Madihally, S.; Toner, M.; Yarmush, M.; Mitchell, R.

    A diverse physiological conditions lead to a hypercatabolic state marked by the loss of proteins, primarily derived from skeletal muscle. The sustained loss of proteins results in loss of muscle mass and strength, poor healing, and long-term hospitalization. These problems are further compounded by the deterioration of immunity to infection which is a leading cause of morbidity and mortality of traumatic patients. In an attempt to understand the signal propagation mechanism(s), we tested the role of Interferon-? (IFN-? ) in an animal burn injury model; IFN-? is best conceptualized as a macrophage activating protein and known to modulate a variety of intracellular processes potentially relevant to muscle wasting and immune dysfunction. Mice congenitally -deficient in IFN-? , and IFN-? -Receptor, and wild type (WT) animals treated with IFN-? neutralizing antibody received either a 20% total body surface area burn or a control sham treatment. At days 1, 2, and 7 following treatment, skeletal muscle, peripheral blood, and spleen were harvested from both groups. Overall body weight, protein turnovers, changes in the lymphocyte subpopulations and alterations in the major histocompatibility complex I expression (MHC I) and proliferation capacity of lymphocytes was measured using mixed lymphocyte reaction (MLR). These results indicate that we can prevent both muscle wasting and immune dysfunction. Based on these observations and our previous other animal model results (using insulin therapy), a novel mechanism of interactions leading to muscle wasting and immune dysfunction will be discussed. Further, implications of these findings on future research and clinical therapies will be discussed in detail.

  4. Metabolic and adaptive immune responses induced in mice infected ...

    African Journals Online (AJOL)

    This study investigated metabolic and immuno-inflammatory responses of mice infected with tissue-dwelling larvae of Trichinella zimbabwensis and explored the relationship between infection, metabolic parameters and Th1/Th17 immune responses. Sixty (60) female BALB/c mice aged between 6 to 8 weeks old were ...

  5. Targeting epigenetic processes in photodynamic therapy-induced anticancer immunity

    Directory of Open Access Journals (Sweden)

    Malgorzata eWachowska

    2015-07-01

    Full Text Available Photodynamic therapy (PDT of cancer is an approved therapeutic procedure that generates oxidative stress leading to cell death of tumour and stromal cells. Cell death resulting from oxidative damage to intracellular components leads to the release of damage-associated molecular patterns (DAMPs that trigger robust inflammatory response and creates local conditions for effective sampling of tumour-associated antigens (TAA by antigen presenting cells. The latter can trigger development of TAA-specific adaptive immune response. However, due to a number of mechanisms, including epigenetic regulation of TAA expression, tumour cells evade immune recognition. Therefore, numerous approaches are being developed to combine PDT with immunotherapies to allow development of systemic immunity. In this review we describe immunoregulatory mechanisms of epigenetic treatments that were shown to restore the expression of epigenetically silenced or down-regulated major histocompatibility complex (MHC molecules as well as TAA. We also discuss the results of our recent studies showing that epigenetic treatments based on administration of methyltransferase inhibitors in combination with photodynamic therapy can release effective mechanisms leading to development of antitumour immunity and potentiated antitumour effects.

  6. Modeling protective anti-tumor immunity via preventative cancer vaccines using a hybrid agent-based and delay differential equation approach.

    Science.gov (United States)

    Kim, Peter S; Lee, Peter P

    2012-01-01

    A next generation approach to cancer envisions developing preventative vaccinations to stimulate a person's immune cells, particularly cytotoxic T lymphocytes (CTLs), to eliminate incipient tumors before clinical detection. The purpose of our study is to quantitatively assess whether such an approach would be feasible, and if so, how many anti-cancer CTLs would have to be primed against tumor antigen to provide significant protection. To understand the relevant dynamics, we develop a two-compartment model of tumor-immune interactions at the tumor site and the draining lymph node. We model interactions at the tumor site using an agent-based model (ABM) and dynamics in the lymph node using a system of delay differential equations (DDEs). We combine the models into a hybrid ABM-DDE system and investigate dynamics over a wide range of parameters, including cell proliferation rates, tumor antigenicity, CTL recruitment times, and initial memory CTL populations. Our results indicate that an anti-cancer memory CTL pool of 3% or less can successfully eradicate a tumor population over a wide range of model parameters, implying that a vaccination approach is feasible. In addition, sensitivity analysis of our model reveals conditions that will result in rapid tumor destruction, oscillation, and polynomial rather than exponential decline in the tumor population due to tumor geometry.

  7. Cytomegalovirus vector expressing RAE-1γ induces enhanced anti-tumor capacity of murine CD8+T cells.

    Science.gov (United States)

    Tršan, Tihana; Vuković, Kristina; Filipović, Petra; Brizić, Ana Lesac; Lemmermann, Niels A W; Schober, Kilian; Busch, Dirk H; Britt, William J; Messerle, Martin; Krmpotić, Astrid; Jonjić, Stipan

    2017-08-01

    Designing CD8 + T-cell vaccines, which would provide protection against tumors is still considered a great challenge in immunotherapy. Here we show the robust potential of cytomegalovirus (CMV) vector expressing the NKG2D ligand RAE-1γ as CD8 + T cell-based vaccine against malignant tumors. Immunization with the CMV vector expressing RAE-1γ, delayed tumor growth or even provided complete protection against tumor challenge in both prophylactic and therapeutic settings. Moreover, a potent tumor control in mice vaccinated with this vector can be further enhanced by blocking the immune checkpoints TIGIT and PD-1. CMV vector expressing RAE-1γ potentiated expansion of KLRG1 + CD8 + T cells with enhanced effector properties. This vaccination was even more efficient in neonatal mice, resulting in the expansion and long-term maintenance of epitope-specific CD8 + T cells conferring robust resistance against tumor challenge. Our data show that immunomodulation of CD8 + T-cell responses promoted by herpesvirus expressing a ligand for NKG2D receptor can provide a powerful platform for the prevention and treatment of CD8 + T-cell sensitive tumors. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. Transplantational and specific antitumor immunity in retrospective view: new models based on transgenesis of individual chains of T-cell receptor

    Directory of Open Access Journals (Sweden)

    D. B. Kazanskiy

    2016-01-01

    Full Text Available Findings in experimental oncology in beginning of last century and subsequent achievements of genetics of tissue compatibility resulted in divergence of transplantational immunology and oncoimmunology. However, central achievements of both scientific fields are based on unified phenomenon of interaction between T-cell receptor (TCR and histocompatibility molecules. In this review we describe the history of ideas, achievements and unique experience of the team of the Laboratory of Regulatory Mechanisms in Immunity at Scientific Research Institute of Carcinogenesis, N.N. Blokhin Russian Cancer Research Center for all time of existence. This experience shows that efficiency of immunological defense including immunological surveillance are critically influenced by T-cell receptor repertoire. Transgenesis of individual chains of TCR is one of possible means to manage T-cell repertoire. Functional outcomes of transgenesis may be different due to diverse extent of dependence of α- and β-chains expression on the rules of allelic exclusion. Expression of transgenic β-chains results in the expansion of TCR repertoire diversity. Expression of β-chains is under strong control by allelic exclusion, resulting in formation of repertoire bearing mainly invariant transgenic β-chain pared with different α-chains and overall narrowing of repertoire. Earlier, we cloned genes encoding α- and β-chains of TCR of CD8+ memory cells specific to histocompatibility molecule H-2Kb . After introduction them in zigotes we have obtained transgenic mouse strains, which could be used for modeling of interactions between tumor cells and immune system of recipient. Normally, B10. D2 (R101 mice reject lymphoma EL4 cells in 12–14 days after transplantation, in spite of the fact, that allogeneic difference between B10. D2 (R101 (Kd Id Db mice and lymphoma EL4 (H-2b cells is only in one product of MHC, the H-2Kb molecule. Transgenics carrying β-chains of TCR displayed

  9. Induction of an antitumor response using dendritic cells transfected with DNA constructs encoding the HLA-A*02:01-restricted epitopes of tumor-associated antigens in culture of mononuclear cells of breast cancer patients.

    Science.gov (United States)

    Sennikov, Sergey Vital'evich; Shevchenko, Julia Alexandrovna; Kurilin, Vasilii Vasil'evich; Khantakova, Julia Nikolaevna; Lopatnikova, Julia Anatol'evna; Gavrilova, Elena Vasil'evna; Maksyutov, Rinat Amirovich; Bakulina, Anastasiya Yur'evna; Sidorov, Sergey Vasil'evich; Khristin, Alexander Alexandrovich; Maksyutov, Amir Zakievich

    2016-02-01

    Advances in oncoimmunology related to the definition of the basic mechanisms of the formation of antitumor immune response, as well as the opening of tumor-associated antigens recognized by immune cells, allowed to start developing ways to influence the effector cells of the immune system to generate effective antitumor cytotoxic response. We investigated the possibility to stimulate an antitumor response in a culture of mononuclear cells of breast cancer patients by dendritic cells transfected with HLA-A*02:01-restricted DNA constructs. We isolated dendritic cells from peripheral blood monocytes and delivered our constructs to these cells by magnetic transfection. Additionally, a series of experiments with loading of dendritic cells with autologous tumor cell lysate antigens was conducted. We have shown that dendritic cells transfected with the HLA-A*02:01-restricted DNA constructs are effective in inducing an antitumor response in a culture of mononuclear cells of breast cancer patients. Dendritic cells transfected with DNA constructor dendritic cells loaded with lysate antigens revealed a comparable stimulated cytotoxic response of mononuclear cells to these two ways of antigen delivery. We conclude that using DNA constructs in conjunction with patient stratification by HLA type allows the application of transfected DCs as an effective method to stimulate antitumor immunity in vitro.

  10. Perillyl alcohol suppresses antigen-induced immune responses in the lung

    International Nuclear Information System (INIS)

    Imamura, Mitsuru; Sasaki, Oh; Okunishi, Katsuhide; Nakagome, Kazuyuki; Harada, Hiroaki; Kawahata, Kimito; Tanaka, Ryoichi; Yamamoto, Kazuhiko; Dohi, Makoto

    2014-01-01

    Highlights: •Perillyl alcohol (POH) is an isoprenoid which inhibits the mevalonate pathway. •We examined whether POH suppresses immune responses with a mouse model of asthma. •POH treatment during sensitization suppressed Ag-induced priming of CD4 + T cells. •POH suppressed airway eosinophila and cytokine production in thoracic lymph nodes. -- Abstract: Perillyl alcohol (POH) is an isoprenoid which inhibits farnesyl transferase and geranylgeranyl transferase, key enzymes that induce conformational and functional changes in small G proteins to conduct signal production for cell proliferation. Thus, it has been tried for the treatment of cancers. However, although it affects the proliferation of immunocytes, its influence on immune responses has been examined in only a few studies. Notably, its effect on antigen-induced immune responses has not been studied. In this study, we examined whether POH suppresses Ag-induced immune responses with a mouse model of allergic airway inflammation. POH treatment of sensitized mice suppressed proliferation and cytokine production in Ag-stimulated spleen cells or CD4 + T cells. Further, sensitized mice received aerosolized OVA to induce allergic airway inflammation, and some mice received POH treatment. POH significantly suppressed indicators of allergic airway inflammation such as airway eosinophilia. Cytokine production in thoracic lymph nodes was also significantly suppressed. These results demonstrate that POH suppresses antigen-induced immune responses in the lung. Considering that it exists naturally, POH could be a novel preventive or therapeutic option for immunologic lung disorders such as asthma with minimal side effects

  11. Platelet activating factor receptor binding plays a critical role in jet fuel-induced immune suppression

    International Nuclear Information System (INIS)

    Ramos, Gerardo; Kazimi, Nasser; Nghiem, Dat X.; Walterscheid, Jeffrey P.; Ullrich, Stephen E.

    2004-01-01

    Applying military jet fuel (JP-8) or commercial jet fuel (Jet-A) to the skin of mice suppresses the immune response in a dose-dependant manner. The release of biological response modifiers, particularly prostaglandin E 2 (PGE 2 ), is a critical step in activating immune suppression. Previous studies have shown that injecting selective cyclooxygenase-2 inhibitors into jet fuel-treated mice blocks immune suppression. Because the inflammatory phospholipid mediator, platelet-activating factor (PAF), up-regulates cyclooxygenase-2 production and PGE 2 synthesis by keratinocytes, we tested the hypothesis that PAF-receptor binding plays a role in jet fuel-induced immune suppression. Treating keratinocyte cultures with PAF and/or jet fuel (JP-8 and Jet-A) stimulates PGE 2 secretion. Jet fuel-induced PGE 2 production was suppressed by treating the keratinocytes with specific PAF-receptor antagonists. Injecting mice with PAF, or treating the skin of the mice with JP-8, or Jet-A, induced immune suppression. Jet fuel-induced immune suppression was blocked when the jet fuel-treated mice were injected with PAF-receptor antagonists before treatment. Jet fuel treatment has been reported to activate oxidative stress and treating the mice with anti-oxidants (Vitamins C, or E or beta-hydroxy toluene), before jet fuel application, interfered with immune suppression. These findings confirm previous studies showing that PAF-receptor binding can modulate immune function. Furthermore, they suggest that PAF-receptor binding may be an early event in the induction of immune suppression by immunotoxic environmental agents that target the skin

  12. Synergistic anti-tumor actions of luteolin and silibinin prevented cell migration and invasion and induced apoptosis in glioblastoma SNB19 cells and glioblastoma stem cells.

    Science.gov (United States)

    Chakrabarti, Mrinmay; Ray, Swapan K

    2015-12-10

    Glioblastoma is the most lethal brain tumor. Failure of conventional chemotherapies prompted the search for natural compounds for treatment of glioblastoma. Plant-derived flavonoids could be alternative medicine for inhibiting not only glioblastoma cells but also glioblastoma stem cells (GSC). Two plant-derived flavonoids are luteolin (LUT) and silibinin (SIL). We investigated anti-tumor mechanisms of LUT and SIL in different human glioblastoma cells and GSC and found significant synergistic inhibition of human glioblastoma LN18 and SNB19 cells and GSC following treatment with combination of 20µM LUT and 50µM SIL. Combination of 20µM LUT and 50µM SIL was more effective than a conventional chemotherapeutic agent (BCNU or TMZ). We continued our studies with SNB19 cells and GSC and found dramatic inhibition of cell migration from spheroids and also cell invasion through matrigel following treatment with combination of LUT and SIL. This combination was highly effective to block angiogenesis and survival pathways leading to induction of apoptosis. Inhibition of PKCα, XIAP, and iNOS ultimately caused induction of extrinsic and intrinsic pathways of apoptosis. Collectively, synergistic efficacy of LUT and SIL could be a promising therapy to inhibit cell migration and invasion and induce apoptosis in different glioblastoma cells including GSC. Copyright © 2015 Elsevier B.V. All rights reserved.

  13. Encapsulation into Stealth Liposomes Enhances the Antitumor Action of Recombinant Cratylia mollis Lectin Expressed in Escherichia coli

    Science.gov (United States)

    da Cunha, Cássia R. A.; da Silva, Luís C. N.; Almeida, Fábio J. F.; Ferraz, Milena S.; Varejão, Nathalia; Cartaxo, Marina F. de Souza; de Miranda, Rita de Cássia M.; de Aguiar, Francisco C. A.; Santos, Noemia P. da Silva; Coelho, Luana C. B. B.; Santos-Magalhães, Nereide S.; Correia, Maria T. dos Santos

    2016-01-01

    This study evaluated the in vivo antitumor potential of the recombinant lectin from seeds of Cratylia mollis (rCramoll) expressed in Escherichia coli, free or encapsulated in stealth liposomes, using mice transplanted with sarcoma 180. rCramoll-loaded stealth liposomes (rCramoll-lipo) were formulated by hydration of the lipid film followed by cycles of freezing and thawing, and about 60% of rCramoll was encapsulated. This novel preparation showed particle size, polydispersity index, and pH suitable for the evaluation of antitumor activity in vivo. Tumor growth inhibition rates were 59% for rCramoll and 75% for rCramoll-lipo. Histopathological analysis of the experimental groups showed that both free and encapsulated lectin caused no changes in the kidneys of animals. Hematological analysis revealed that treatment with rCramoll-lipo significantly increased leukocyte concentration when compared with the untreated and rCramoll group. In conclusion, the encapsulation of rCramoll in stealth liposomes improves its antitumor activity without substantial toxicity; this approach was more successful than the previous results reported for pCramoll loaded into conventional liposomes. At this point, a crucial difference between the antitumor action of free and encapsulated rCramoll was found along with their effects on immune cells. Further investigations are required to elucidate the mechanism(s) of the antitumor effect induced by rCramoll. PMID:27695439

  14. Vector transmission of leishmania abrogates vaccine-induced protective immunity.

    Directory of Open Access Journals (Sweden)

    Nathan C Peters

    2009-06-01

    Full Text Available Numerous experimental vaccines have been developed to protect against the cutaneous and visceral forms of leishmaniasis caused by infection with the obligate intracellular protozoan Leishmania, but a human vaccine still does not exist. Remarkably, the efficacy of anti-Leishmania vaccines has never been fully evaluated under experimental conditions following natural vector transmission by infected sand fly bite. The only immunization strategy known to protect humans against natural exposure is "leishmanization," in which viable L. major parasites are intentionally inoculated into a selected site in the skin. We employed mice with healed L. major infections to mimic leishmanization, and found tissue-seeking, cytokine-producing CD4+ T cells specific for Leishmania at the site of challenge by infected sand fly bite within 24 hours, and these mice were highly resistant to sand fly transmitted infection. In contrast, mice vaccinated with a killed vaccine comprised of autoclaved L. major antigen (ALM+CpG oligodeoxynucleotides that protected against needle inoculation of parasites, showed delayed expression of protective immunity and failed to protect against infected sand fly challenge. Two-photon intra-vital microscopy and flow cytometric analysis revealed that sand fly, but not needle challenge, resulted in the maintenance of a localized neutrophilic response at the inoculation site, and removal of neutrophils following vector transmission led to increased parasite-specific immune responses and promoted the efficacy of the killed vaccine. These observations identify the critical immunological factors influencing vaccine efficacy following natural transmission of Leishmania.

  15. Role of MicroRNAs in Obesity-Induced Metabolic Disorder and Immune Response

    Directory of Open Access Journals (Sweden)

    Hong Zhong

    2018-01-01

    Full Text Available In all living organisms, metabolic homeostasis and the immune system are the most fundamental requirements for survival. Recently, obesity has become a global public health issue, which is the cardinal risk factor for metabolic disorder. Many diseases emanating from obesity-induced metabolic dysfunction are responsible for the activated immune system, including innate and adaptive responses. Of note, inflammation is the manifest accountant signal. Deeply studied microRNAs (miRNAs have participated in many pathways involved in metabolism and immune responses to protect cells from multiple harmful stimulants, and they play an important role in determining the progress through targeting different inflammatory pathways. Thus, immune response and metabolic regulation are highly integrated with miRNAs. Collectively, miRNAs are the new targets for therapy in immune dysfunction.

  16. An alphavirus vector-based tetravalent dengue vaccine induces a rapid and protective immune response in macaques that differs qualitatively from immunity induced by live virus infection.

    Science.gov (United States)

    White, Laura J; Sariol, Carlos A; Mattocks, Melissa D; Wahala M P B, Wahala; Yingsiwaphat, Vorraphun; Collier, Martha L; Whitley, Jill; Mikkelsen, Rochelle; Rodriguez, Idia V; Martinez, Melween I; de Silva, Aravinda; Johnston, Robert E

    2013-03-01

    Despite many years of research, a dengue vaccine is not available, and the more advanced live attenuated vaccine candidate in clinical trials requires multiple immunizations with long interdose periods and provides low protective efficacy. Here, we report important contributions to the development of a second-generation dengue vaccine. First, we demonstrate that a nonpropagating vaccine vector based on Venezuelan equine encephalitis virus replicon particles (VRP) expressing two configurations of dengue virus E antigen (subviral particles [prME] and soluble E dimers [E85]) successfully immunized and protected macaques against dengue virus, while antivector antibodies did not interfere with a booster immunization. Second, compared to prME-VRP, E85-VRP induced neutralizing antibodies faster, to higher titers, and with improved protective efficacy. Third, this study is the first to map antigenic domains and specificities targeted by vaccination versus natural infection, revealing that, unlike prME-VRP and live virus, E85-VRP induced only serotype-specific antibodies, which predominantly targeted EDIII, suggesting a protective mechanism different from that induced by live virus and possibly live attenuated vaccines. Fourth, a tetravalent E85-VRP dengue vaccine induced a simultaneous and protective response to all 4 serotypes after 2 doses given 6 weeks apart. Balanced responses and protection in macaques provided further support for exploring the immunogenicity and safety of this vaccine candidate in humans.

  17. An Alphavirus Vector-Based Tetravalent Dengue Vaccine Induces a Rapid and Protective Immune Response in Macaques That Differs Qualitatively from Immunity Induced by Live Virus Infection

    Science.gov (United States)

    Sariol, Carlos A.; Mattocks, Melissa D.; Wahala M. P. B., Wahala; Yingsiwaphat, Vorraphun; Collier, Martha L.; Whitley, Jill; Mikkelsen, Rochelle; Rodriguez, Idia V.; Martinez, Melween I.; de Silva, Aravinda; Johnston, Robert E.

    2013-01-01

    Despite many years of research, a dengue vaccine is not available, and the more advanced live attenuated vaccine candidate in clinical trials requires multiple immunizations with long interdose periods and provides low protective efficacy. Here, we report important contributions to the development of a second-generation dengue vaccine. First, we demonstrate that a nonpropagating vaccine vector based on Venezuelan equine encephalitis virus replicon particles (VRP) expressing two configurations of dengue virus E antigen (subviral particles [prME] and soluble E dimers [E85]) successfully immunized and protected macaques against dengue virus, while antivector antibodies did not interfere with a booster immunization. Second, compared to prME-VRP, E85-VRP induced neutralizing antibodies faster, to higher titers, and with improved protective efficacy. Third, this study is the first to map antigenic domains and specificities targeted by vaccination versus natural infection, revealing that, unlike prME-VRP and live virus, E85-VRP induced only serotype-specific antibodies, which predominantly targeted EDIII, suggesting a protective mechanism different from that induced by live virus and possibly live attenuated vaccines. Fourth, a tetravalent E85-VRP dengue vaccine induced a simultaneous and protective response to all 4 serotypes after 2 doses given 6 weeks apart. Balanced responses and protection in macaques provided further support for exploring the immunogenicity and safety of this vaccine candidate in humans. PMID:23302884

  18. Canine distemper virus-immune complexes induce bystander degeneration of oligodendrocytes.

    Science.gov (United States)

    Botteron, C; Zurbriggen, A; Griot, C; Vandevelde, M

    1992-01-01

    Demyelination in chronic canine distemper encephalitis may be the result of a bystander effect in which the antiviral immune response is involved. In the present report we demonstrate that canine distemper virus-antiviral antibody immune complexes induce oligodendroglial degeneration in mixed brain cell cultures, particularly at the level of the cell processes. The involvement of macrophages as effector cells in this process was confirmed by depletion of these cells from the cultures which prevented the immune complex-mediated oligodendroglial degeneration. Canine distemper virus-immune complex-induced oligodendroglial pathology is thought to be mediated by toxic factors released from stimulated macrophages, this bystander effect demonstrated here in vitro may be relevant to the mechanisms of demyelination in vivo, in which virus persistence plays an important role.

  19. Anti-tumor and immunomodulatory activities of an exopolysaccharide from Rhizopus nigricans on CT26 tumor-bearing mice.

    Science.gov (United States)

    Zhu, Lei; Cao, Jianfeng; Chen, Guochuang; Xu, Yanghui; Lu, Jingbo; Fang, Fang; Chen, Kaoshan

    2016-07-01

    This study was aimed to investigate the anti-tumor and immunomodulatory activities of an exopolysaccharide (EPS) from Rhizopus nigricans. Our results showed EPS could significantly inhibit the tumor growth and increase the immune organs index of CT26 tumor-bearing mice. EPS treatment increased the productions of interleukin-2 (IL-2) and tumor necrosis factor-α (TNF-α) levels in serum. The increase of percentage of CD8(+) cytotoxic T cells among total spleen T lymphocyte was also observed. Furthermore, EPS remarkably stimulate spleen lymphocytes proliferation in the absence or presence of mitogens. In addition, we found that EPS had synergistic effect with chemotherapy and improved immunosuppressive effect induced by 5-Fu. In summary, these findings indicated that the antitumor effects of EPS might be partly due to immune function activation and it might have potential to be used in the treatment for colorectal cancer. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. Properties of a non-bioactive fluorescent derivative of differentiation-inducing factor-3, an anti-tumor agent found in Dictyostelium discoideum

    Science.gov (United States)

    Kubohara, Yuzuru; Kikuchi, Haruhisa; Matsuo, Yusuke; Oshima, Yoshiteru; Homma, Yoshimi

    2014-01-01

    ABSTRACT Differentiation-inducing factor-3 (DIF-3), found in the cellular slime mold Dictyostelium discoideum, and its derivatives, such as butoxy-DIF-3 (Bu-DIF-3), are potent anti-tumor agents. To investigate the activity of DIF-like molecules in tumor cells, we recently synthesized a green fluorescent DIF-3 derivative, BODIPY-DIF-3G, and analyzed its bioactivity and cellular localization. In this study, we synthesized a red (orange) fluorescent DIF-3 derivative, BODIPY-DIF-3R, and compared the cellular localization and bioactivities of the two BODIPY-DIF-3s in HeLa human cervical cancer cells. Both fluorescent compounds penetrated the extracellular membrane within 0.5 h and localized mainly to the mitochondria. In formalin-fixed cells, the two BODIPY-DIF-3s also localized to the mitochondria, indicating that the BODIPY-DIF-3s were incorporated into mitochondria independently of the mitochondrial membrane potential. After treatment for 3 days, BODIPY-DIF-3G, but not BODIPY-DIF-3R, induced mitochondrial swelling and suppressed cell proliferation. Interestingly, the swollen mitochondria were stainable with BODIPY-DIF-3G but not with BODIPY-DIF-3R. When added to isolated mitochondria in vitro, BODIPY-DIF-3G increased dose-dependently the rate of O2 consumption, but BODIPY-DIF-3R did not. These results suggest that the bioactive BODIPY-DIF-3G suppresses cell proliferation, at least in part, by altering mitochondrial activity, whereas the non-bioactive BODIPY-DIF-3R localizes to the mitochondria but does not affect mitochondrial activity or cell proliferation. PMID:24682009

  1. Pre-clinical toxicity and immunogenicity evaluation of a MUC1-MBP/BCG anti-tumor vaccine.

    Science.gov (United States)

    Hu, Boqi; Wang, Juan; Guo, Yingying; Chen, Tanxiu; Ni, Weihua; Yuan, Hongyan; Zhang, Nannan; Xie, Fei; Tai, Guixiang

    2016-04-01

    Mucin 1 (MUC1), as an oncogene, plays a key role in the progression and tumorigenesis of many human adenocarcinomas and is an attractive target in tumor immunotherapy. Our previous study showed that the MUC1-MBP/BCG anti-tumor vaccine induced a MUC1-specific Th1-dominant immune response, simulated MUC1-specific cytotoxic T lymphocyte killing activity, and could significantly inhibit MUC1-expression B16 cells' growth in mice. To help move the vaccine into a Phase I clinical trial, in the current study, a pre-clinical toxicity and immunogenicity evaluation of the vaccine was conducted. The evaluation was comprised of a single-dose acute toxicity study in mice, repeat-dose chronic toxicity and immunogenicity studies in rats, and pilot toxicity and immunogenicity studies in cynomolgus monkeys. The results showed that treatment with the MUC1-MBP/BCG anti-tumor vaccine did not cause any organ toxicity, except for arthritis or local nodules induced by BCG in several rats. Furthermore, the vaccine significantly increased the levels of IFN-γ in rats, indicating that Th1 cells were activated. In addition, the results showed that the MUC1-MBP/BCG anti-tumor vaccine induced a MUC1-specific IgG antibody response both in rats and cynomolgus monkeys. Collectively, these data are beneficial to move the MUC1-MBP/BCG anti-tumor vaccine into a Phase I clinical trial. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. Lactogenic immunity to transmissible gastroenteritis virus induced by a subunit immunogen.

    Science.gov (United States)

    Gough, P M; Frank, C J; Moore, D G; Sagona, M A; Johnson, C J

    1983-12-01

    A subunit prepared from transmissible gastroenteritis (TGE) virus and used to immunize 24 gilts prior to farrowing induced production of specific antibody in the serum and milk. Challenge of pigs, two to seven days of age and suckling on the vaccinated gilts, with the Illinois strain of TGE virus resulted in morbidity of 28% and mortality of 4% as compared with 100 and 73%, respectively, for control piglets. Piglets nursing on a sow which had been immunized approximately 10 months previously were not protected, indicating that lactogenic immunity may be of short duration. Revaccination of this animal resulted in an anamnestic response.

  3. The skin microbiome: Is it affected by UV-induced immune suppression?

    Directory of Open Access Journals (Sweden)

    Vijaykumar Patra

    2016-08-01

    Full Text Available Human skin apart from functioning as a physical barricade to stop the entry of pathogens, also hosts innumerable commensal organisms. The skin cells and the immune system constantly interact with microbes, to maintain cutaneous homeostasis, despite the challenges offered by various environmental factors. A major environmental factor affecting the skin is ultraviolet radiation UV-R from sunlight. UV-R is well known to modulate the immune system, which can be both beneficial and deleterious. By targeting the cells and molecules within skin, UV-R can trigger the production and release of antimicrobial peptides (AMPs, affect the innate immune system and ultimately suppress the adaptive cellular immune response. This can contribute to skin carcinogenesis and the promotion of infectious agents such as herpes simplex virus and possibly others. On the other hand, a UV-established immunosuppressive environment may protect against the induction of immunologically mediated skin diseases including some of photodermatoses such as polymorphic light eruption. In this article, we share our perspective about the possibility that UV-induced immune suppression may alter the landscape of the skin's microbiome and its components. Alternatively, or in concert with this, direct UV-induced DNA and membrane damage to the microbiome may result in pathogen associated molecular patterns (PAMPs that interfere with UV-induced immune suppression.

  4. Stress/aggressiveness-induced immune changes are altered in adult rats submitted to neonatal malnutrition.

    Science.gov (United States)

    Barreto-Medeiros, Jairza; Queiros-Santos, Adenilda; Cabral-Filho, José Eulálio; Ferreira E Silva, Wylla Tatiana; Leandro, Carol Góis; Deiró, Tereza Cristina; Manhaes-de-Castro, Raul; Machado Barbosa de-Castro, Célia Maria

    2007-01-01

    Neonatal malnutrition induces metabolic and endocrine changes that have beneficial effects on the neonatal in the short term but, in the longer term, these alterations lead to maladaptations. We investigated the effect of neonatal malnutrition on immune responses in adult rats submitted or not to an aggressiveness test. Male Wistar rats were distributed to one of two groups according to their mothers' diet during lactation: the well-nourished group (group C, n = 42, receiving 23% of protein) and the malnourished group (group MN, n = 42, receiving 8% of protein). After weaning, all rats received normoproteic diet. Ninety days after birth, each group was subdivided into three subgroups: control rats (n = 14, respectively), aggressive rats (n = 14, respectively) and rats receiving foot shock (FS; n = 14, respectively). Plasma corticosterone concentration was measured after FS sessions. Leukocyte counts and humoral immunity were evaluated. In neonatal malnourished animals, FS-induced stress reduced plasma corticosterone concentration. Intraspecific aggressiveness induced alterations in leukocyte counts and antibody titers 7 and 15 days after immunization. Neonatal malnourished animals showed no changes in the immune parameters evaluated. Expression of intraspecific aggressiveness activates the immune system. Neonatal malnutrition seems to have a long-lasting effect on components of both neuroendocrine and immune functions.

  5. Identification of hub genes related to silicone-induced immune response in rats.

    Science.gov (United States)

    Huang, Xiaolu; Zhou, Yiwen; Liu, Wenhui; Li, Haizhou; Liang, Xiao; Jin, Rui; Du, Hengyu; He, Jizhou; Chai, Bangda; Duan, Ran; Li, Qingfeng

    2017-11-21

    Silicone implants are used widely in the field of plastic surgery and are used in a large population. However, their safety profile, especially the silicone-induced immune response, has been a major concern for plastic surgeons for decades. It has been hypothesized that there is a cause and effect relation between silicone and immunity, but this is controversial. The objective of the present study was to determine the hub genes and key pathways related to silicone implant-induced immune responses in a rat model. In addition to cluster and enrichment analyses, we used weighted gene co-expression network analysis (WGCNA) to examine the gene expression profiles in a systematic context. A total five genes ( Fes , Aif1 , Gata3 , Tlr6 , Tlr2 ) were identified as hub genes that are most likely related to the silicone-induced immune response, four of which ( Aif1 , Gata3 , Tlr6 , Tlr2 ) have been associated with autoimmunity as target genes or disease markers. The Toll-like receptor signaling pathway ( p silicone-implanted skin samples. The results indicate that silicone implants might trigger the localized immune response, as various immune reaction genes were detected after silicone implantation. The identified five hub genes will hopefully serve as novel therapeutic targets for silicone-related complications and the associated autoimmune diseases.

  6. The fully synthetic MAG-Tn3 therapeutic vaccine containing the tetanus toxoid-derived TT830-844 universal epitope provides anti-tumor immunity.

    Science.gov (United States)

    Laubreton, Daphné; Bay, Sylvie; Sedlik, Christine; Artaud, Cécile; Ganneau, Christelle; Dériaud, Edith; Viel, Sophie; Puaux, Anne-Laure; Amigorena, Sebastian; Gérard, Catherine; Lo-Man, Richard; Leclerc, Claude

    2016-03-01

    Malignant transformations are often associated with aberrant glycosylation processes that lead to the expression of new carbohydrate antigens at the surface of tumor cells. Of these carbohydrate antigens, the Tn antigen is particularly highly expressed in many carcinomas, especially in breast carcinoma. We designed MAG-Tn3, a fully synthetic vaccine based on three consecutive Tn moieties that are O-linked to a CD4+ T cell epitope, to induce anti-Tn antibody responses that could be helpful for therapeutic vaccination against cancer. To ensure broad coverage within the human population, the tetanus toxoid-derived peptide TT830-844 was selected as a T-helper epitope because it can bind to various HLA-DRB molecules. We showed that the MAG-Tn3 vaccine, which was formulated with the GSK proprietary immunostimulant AS15 and designed for human cancer therapy, is able to induce an anti-Tn antibody response in mice of various H-2 haplotypes, and this response correlates with the ability to induce a specific T cell response against the TT830-844 peptide. The universality of the TT830-844 peptide was extended to new H-2 and HLA-DRB molecules that were capable of binding this T cell epitope. Finally, the MAG-Tn3 vaccine was able to induce anti-Tn antibody responses in cynomolgus monkeys, which targeted Tn-expressing tumor cells and mediated tumor cell death both in vitro and in vivo. Thus, MAG-Tn3 is a highly promising anticancer vaccine that is currently under evaluation in a phase I clinical trial.

  7. Strain-specific protective effect of the immunity induced by live malarial sporozoites under chloroquine cover.

    Science.gov (United States)

    Wijayalath, Wathsala; Cheesman, Sandra; Tanabe, Kazuyuki; Handunnetti, Shiroma; Carter, Richard; Pathirana, Sisira

    2012-01-01

    The efficacy of a whole-sporozoite malaria vaccine would partly be determined by the strain-specificity of the protective responses against malarial sporozoites and liver-stage parasites. Evidence from previous reports were inconsistent, where some studies have shown that the protective immunity induced by irradiated or live sporozoites in rodents or humans were cross-protective and in others strain-specific. In the present work, we have studied the strain-specificity of live sporozoite-induced immunity using two genetically and immunologically different strains of Plasmodium cynomolgi, Pc746 and PcCeylon, in toque monkeys. Two groups of monkeys were immunized against live sporozoites of either the Pc746 (n = 5), or the PcCeylon (n = 4) strain, by the bites of 2-4 sporozoite-infected Anopheles tessellates mosquitoes per monkey under concurrent treatments with chloroquine and primaquine to abrogate detectable blood infections. Subsequently, a group of non-immunized monkeys (n = 4), and the two groups of immunized monkeys were challenged with a mixture of sporozoites of the two strains by the bites of 2-5 infective mosquitoes from each strain per monkey. In order to determine the strain-specificity of the protective immunity, the proportions of parasites of the two strains in the challenge infections were quantified using an allele quantification assay, Pyrosequencing™, based on a single nucleotide polymorphism (SNP) in the parasites' circumsporozoite protein gene. The Pyrosequencing™ data showed that a significant reduction of parasites of the immunizing strain in each group of strain-specifically immunized monkeys had occurred, indicating a stronger killing effect on parasites of the immunizing strain. Thus, the protective immunity developed following a single, live sporozoite/chloroquine immunization, acted specifically against the immunizing strain and was, therefore, strain-specific. As our experiment does not allow us to determine the parasite stage at

  8. Cisplatin as an Anti-Tumor Drug: Cellular Mechanisms of Activity, Drug Resistance and Induced Side Effects

    International Nuclear Information System (INIS)

    Florea, Ana-Maria; Büsselberg, Dietrich

    2011-01-01

    Platinum complexes are clinically used as adjuvant therapy of cancers aiming to induce tumor cell death. Depending on cell type and concentration, cisplatin induces cytotoxicity, e.g., by interference with transcription and/or DNA replication mechanisms. Additionally, cisplatin damages tumors via induction of apoptosis, mediated by the activation of various signal transduction pathways, including calcium signaling, death receptor signaling, and the activation of mitochondrial pathways. Unfortunately, neither cytotoxicity nor apoptosis are exclusively induced in cancer cells, thus, cisplatin might also lead to diverse side-effects such as neuro- and/or renal-toxicity or bone marrow-suppression. Moreover, the binding of cisplatin to proteins and enzymes may modulate its biochemical mechanism of action. While a combination-chemotherapy with cisplatin is a cornerstone for the treatment of multiple cancers, the challenge is that cancer cells could become cisplatin-resistant. Numerous mechanisms of cisplatin resistance were described including changes in cellular uptake, drug efflux, increased detoxification, inhibition of apoptosis and increased DNA repair. To minimize cisplatin resistance, combinatorial therapies were developed and have proven more effective to defeat cancers. Thus, understanding of the biochemical mechanisms triggered by cisplatin in tumor cells may lead to the design of more efficient platinum derivates (or other drugs) and might provide new therapeutic strategies and reduce side effects

  9. Immune Cells and Molecular Networks in Experimentally Induced Pulpitis.

    Science.gov (United States)

    Renard, E; Gaudin, A; Bienvenu, G; Amiaud, J; Farges, J C; Cuturi, M C; Moreau, A; Alliot-Licht, B

    2016-02-01

    Dental pulp is a dynamic tissue able to resist external irritation during tooth decay by using immunocompetent cells involved in innate and adaptive responses. To better understand the immune response of pulp toward gram-negative bacteria, we analyzed biological mediators and immunocompetent cells in rat incisor pulp experimentally inflamed by either lipopolysaccharide (LPS) or saline solution (phosphate-buffered saline [PBS]). Untreated teeth were used as control. Expression of pro- and anti-inflammatory cytokines, chemokine ligands, growth factors, and enzymes were evaluated at the transcript level, and the recruitment of the different leukocytes in pulp was measured by fluorescence-activated cell-sorting analysis after 3 h, 9 h, and 3 d post-PBS or post-LPS treatment. After 3 d, injured rat incisors showed pulp wound healing and production of reparative dentin in both LPS and PBS conditions, testifying to the reversible pulpitis status of this model. IL6, IL1-β, TNF-α, CCL2, CXCL1, CXCL2, MMP9, and iNOS gene expression were significantly upregulated after 3 h of LPS stimulation as compared with PBS. The immunoregulatory cytokine IL10 was also upregulated after 3 h, suggesting that LPS stimulates not only inflammation but also immunoregulation. Fluorescence-activated cell-sorting analysis revealed a significant, rapid, and transient increase in leukocyte levels 9 h after PBS and LPS stimulation. The quantity of dendritic cells was significantly upregulated with LPS versus PBS. Interestingly, we identified a myeloid-derived suppressor cell-enriched cell population in noninjured rodent incisor dental pulp. The percentage of this population, known to regulate immune response, was higher 9 h after inflammation triggered with PBS and LPS as compared with the control. Taken together, these data offer a better understanding of the mechanisms involved in the regulation of dental pulp immunity that may be elicited by gram-negative bacteria. © International & American

  10. Severe Pulmonary Arterial Hypertension Induced by SU5416 and Ovalbumin Immunization

    Science.gov (United States)

    Mizuno, Shiro; Farkas, Laszlo; Al Husseini, Aysar; Farkas, Daniela; Gomez-Arroyo, Jose; Kraskauskas, Donatas; Nicolls, Mark R.; Cool, Carlyne D.; Bogaard, Herman J.

    2012-01-01

    The combination of chronic hypoxia and treatment of rats with the vascular endothelial growth factor (VEGF) receptor blocker, SU5416, induces pulmonary angio-obliteration, resulting in severe pulmonary arterial hypertension (PAH). Inflammation is thought to contribute to the pathology of PAH. Allergic inflammation caused by ovalbumin (OVA) immunization causes muscularization of pulmonary arteries, but not severe PAH. Whether disturbance of the immune system and allergic inflammation in the setting of lung endothelial cell apoptosis causes PAH is unknown. We investigated the effects of OVA-allergic inflammation on the development of PAH initiated by VEGF blockade–induced lung endothelial cell apoptosis. OVA-immunized rats were treated with SU5416 to induce pulmonary vascular endothelial cell apoptosis. The combination of OVA and SU5416 treatment resulted in severe angio-obilterative PAH, accompanied by increased IL-6 expression in the lungs. c-Kit+ and Sca-1+ cells were found in and around the lung vascular lesions. Pan-caspase inhibiton, dexamethasone treatment, and depletion of B-lymphocytes using an anti-CD20 antibody suppressed this remodeling. OVA immunization also increased lung tissue hypoxia-induced factor-1α and VEGF expression. Our results also suggest that the increased expression of hypoxia-induced factor-1α and IL-6 induced by the allergic lung inflammation may be a component of the pathogenesis of PAH. PMID:22842496

  11. Topical calcitriol protects from UV-induced genetic damage but suppresses cutaneous immunity in humans.

    Science.gov (United States)

    Damian, Diona L; Kim, Young Jin; Dixon, Katie M; Halliday, Gary M; Javeri, Arash; Mason, Rebecca S

    2010-08-01

    Calcitriol, the biologically active form of vitamin D, has been reported to cause both suppressive and protective immune effects in mice. Its immune effects in vivo in humans are unclear. We investigated the in vivo effects of topical calcitriol on minimal erythema dose and skin immune responses in healthy volunteers. We found that calcitriol did not protect from ultraviolet (UV)-induced erythema (sunburn) when applied either 24 h before or immediately after irradiation, although it decreased the density of sunburn cells and thymine dimers seen on biopsy when applied 24 h before and again immediately after irradiation. Using the Mantoux reaction as a model of skin immunity, we found that topical calcitriol applied at high total doses reduced the Mantoux responses of nearby untreated, unirradiated skin, suggesting a para-local or systemic immunosuppressive effect not observed with lower calcitriol doses. We then measured UV-induced suppression of Mantoux reactions at vehicle-treated sites and sites treated with low-dose calcitriol, and found that calcitriol neither reduced nor enhanced UV-induced immunosuppression. Despite calcitriol reducing UV-induced DNA damage, which should protect the immune system, it has immunosuppressive effects in our model which may help to explain the efficacy of analogues such as calcipotriol in the treatment of psoriasis.

  12. [Antitumor effect of polysaccharides from cactus pear fruit in S180-bearing mice].

    Science.gov (United States)

    Liang, Bei-Bei; Liu, Hua-Gang; Cao, Jiu-Tao

    2008-06-01

    Polysaccharide components of some traditional Chinese medicine have certain antitumor effects and can promote immune responses. Extractions from cactus pear fruit can inhibit the proliferation of cervical cancer, ovary cancer and bladder cancer cells, and suppress the growth of ovarian cancer in mice. This study was to observe the antitumor effect of polysaccharides extracted from cactus pear fruit in S180-bearing mice. S180-bearing mice were established and divided into five groups: normal saline (NS) group, cyclophosphamide (CTX) group, high, middle and low dose of polysaccharide groups. Tumor inhibition rates, values of thymus index, spleen index, superoxide dismutase (SOD), maleic dialdehyde (MDA) and nitrogen monoxidum (NO) were recorded. Changes in ultra-structures of tumor cells under transmission electron microscopy were observed. The tumor inhibition rates in CTX group, high, middle and low dose groups were 7.78%, 31.13%%, 49.70%, 61.07%, respectively. The thymus index was significantly higher in middle and high dose groups than in NS group [(2.61+/-0.43) mg x g(-1) and (2.65+/-0.73) mg x g(-1) vs. (2.22+/-0.24) mg x g(-1), Ppolysaccharide or CTX treated tumor cells showed typical morphology of early apoptosis with condensed chromatin at the margins of nuclei, disintegrated nucleolus and vacuoles in the cytoplasm. Polysaccharides extracted from cactus pear fruit possess certain antitumor effects, which can induce apoptosis, increase antioxidation and promote immune responses.

  13. Toll-like receptor 3-induced immune response by poly(d,l-lactide-co-glycolide) nanoparticles for dendritic cell-based cancer immunotherapy.

    Science.gov (United States)

    Han, Hee Dong; Byeon, Yeongseon; Kang, Tae Heung; Jung, In Duk; Lee, Jeong-Won; Shin, Byung Cheol; Lee, Young Joo; Sood, Anil K; Park, Yeong-Min

    Dendritic cells (DCs) are potent professional antigen-presenting cells that are capable of initiating a primary immune response and activating T cells, and they play a pivotal role in the immune responses of the host to cancer. Prior to antigen presentation, efficient antigen and adjuvant uptake by DCs is necessary to induce their maturation and cytokine generation. Nanoparticles (NPs) are capable of intracellular delivery of both antigen and adjuvant to DCs. Here, we developed an advanced poly(d,l-lactide-co-glycolide) (PLGA)-NP encapsulating both ovalbumin (OVA) as a model antigen and polyinosinic-polycytidylic acid sodium salt (Toll-like receptor 3 ligand) as an adjuvant to increase intracellular delivery and promote DC maturation. The PLGA-NPs were taken up by DCs, and their uptake greatly facilitated major histocompatibility class I antigen presentation in vitro. Moreover, vaccination with PLGA-NP-treated DCs led to the generation of ovalbumin-specific CD8 + T cells, and the resulting antitumor efficacy was significantly increased in EG.7 and TC-1 tumor-bearing mice compared to control mice ( P effective method for delivering tumor-specific antigens or adjuvants to DCs.

  14. Bifidobacterial recombinant thymidine kinase-ganciclovir gene therapy system induces FasL and TNFR2 mediated antitumor apoptosis in solid tumors

    International Nuclear Information System (INIS)

    Wang, Changdong; Ma, Yongping; Hu, Qiongwen; Xie, Tingting; Wu, Jiayan; Zeng, Fan; Song, Fangzhou

    2016-01-01

    Directly targeting therapeutic suicide gene to a solid tumor is a hopeful approach for cancer gene therapy. Treatment of a solid tumor by an effective vector for a suicide gene remains a challenge. Given the lack of effective treatments, we constructed a bifidobacterial recombinant thymidine kinase (BF-rTK) -ganciclovir (GCV) targeting system (BKV) to meet this requirement and to explore antitumor mechanisms. Bifidobacterium (BF) or BF-rTK was injected intratumorally with or without ganciclovir in a human colo320 intestinal xenograft tumor model. The tumor tissues were analyzed using apoptosis antibody arrays, real time PCR and western blot. The colo320 cell was analyzed by the gene silencing method. Autophagy and necroptosis were also detected in colo320 cell. Meanwhile, three human digestive system xenograft tumor models (colorectal cancer colo320, gastric cancer MKN-45 and liver cancer SSMC-7721) and a breast cancer (MDA-MB-231) model were employed to validate the universality of BF-rTK + GCV in solid tumor gene therapy. The survival rate was evaluated in three human cancer models after the BF-rTK + GCV intratumor treatment. The analysis of inflammatory markers (TNF-α) in tumor indicated that BF-rTK + GCV significantly inhibited TNF-α expression. The results suggested that BF-rTK + GCV induced tumor apoptosis without autophagy and necroptosis occurrence. The apoptosis was transduced by multiple signaling pathways mediated by FasL and TNFR2 and mainly activated the mitochondrial control of apoptosis via Bid and Bim, which was rescued by silencing Bid or/and Bim. However, BF + GCV only induced apoptosis via Fas/FasL signal pathway accompanied with increased P53 expression. We further found that BF-rTK + GCV inhibited the expression of the inflammatory maker of TNF-α. However, BF-rTK + GCV did not result in necroptosis and autophagy. BF-rTK + GCV induced tumor apoptosis mediated by FasL and TNFR2 through the mitochondrial control of apoptosis via Bid and Bim

  15. Immune roles of dendritic cells in stem cell transplantation.

    Science.gov (United States)

    Zhang, Cheng; Liao, Wenwei; Liu, Furong; Zhu, Xiaofeng; He, Xiaoshun; Hu, Anbin

    2017-11-01

    Dendritic cells (DCs) are professional antigen-presenting cells and initial stimulators for immune response. DCs can shape their functions based on their immune states, which are crucial for the balance of immunity and tolerance to preserve homeostasis. In the immune response involved in stem cell transplantation, DCs also play important roles in inducing immune tolerance and antitumor immunity. After the rapid development of stem cell transplantation technology in recent years, the risks of graft rejection, tumor recurrence, and tumorigenicity are still present after stem cell transplantation. It is important to understand the mechanisms of DC-mediated immune tolerance and stimulation during stem cell transplantation. In this review, we will summarize and analyze the regulatory mechanisms of DCs in stem cell transplantation and their application in clinical settings. It may help to promote the innovation in basic theories and therapeutic approaches of stem cell transplantation. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. Photodynamic therapy induces an immune response against a bacterial pathogen

    Science.gov (United States)

    Huang, Ying-Ying; Tanaka, Masamitsu; Vecchio, Daniela; Garcia-Diaz, Maria; Chang, Julie; Morimoto, Yuji; Hamblin, Michael R

    2012-01-01

    Photodynamic therapy (PDT) employs the triple combination of photosensitizers, visible light and ambient oxygen. When PDT is used for cancer, it has been observed that both arms of the host immune system (innate and adaptive) are activated. When PDT is used for infectious disease, however, it has been assumed that the direct antimicrobial PDT effect dominates. Murine arthritis caused by methicillin-resistant Staphylococcus aureus in the knee failed to respond to PDT with intravenously injected Photofrin®. PDT with intra-articular Photofrin produced a biphasic dose response that killed bacteria without destroying host neutrophils. Methylene blue was the optimum photosensitizer to kill bacteria while preserving neutrophils. We used bioluminescence imaging to noninvasively monitor murine bacterial arthritis and found that PDT with intra-articular methylene blue was not only effective, but when used before infection, could protect the mice against a subsequent bacterial challenge. The data emphasize the importance of considering the host immune response in PDT for infectious disease. PMID:22882222

  17. Antitumor and immunomodulatory activity of Inonotus obliquus

    Directory of Open Access Journals (Sweden)

    Staniszewska Justyna

    2017-06-01

    Full Text Available The article presents the antitumor and immunomodulatory activity of compounds and extracts from Inonotus obliquus. Polysaccharides isolated from sclerotium have a direct antitumor effect due to protein synthesis inhibition in tumor cells. Polysaccharides derived from the mycelium function by activating the immune system. Due to the limited toxicity of these substances, both extracts as well as isolated and purified chemicals may be a good alternative to current chemotherapy and play a role in cancer prevention. In vitro experiments have shown the inhibition of inflammation with the influence of action of I. obliquus extracts; however, in vivo experiments on animals implanted with tumor cells of different types have shown the activation of the host immune system. This led to decrease in tumor mass and prolonged survival. The immunomodulatory mechanism of action is complex and it seems that stimulation of macrophages and induction of apoptosis in cancer cells is of great importance.

  18. Different immunization routes induce protection against Aeromonas salmonicida through different immune mechanisms in rainbow trout

    DEFF Research Database (Denmark)

    Villumsen, Kasper Rømer; Raida, Martin Kristian

    in fish immunology and vaccinology, resulting in the development of both oral, immersion and injectable vaccine strategies over time. Applying mineral oil adjuvants, injectable vaccines inducing high levels of protection in salmon (Salmo salar) rose to prominence in the 1990’s. In general injectable......, adjuvanted vaccines have been shown to induce long-lasting increases in specific antibody levels. In general the majority of the published work concerning vaccination against A. salmonicida has been conducted on salmon. Using injectable oil-adjuvanted vaccines, we have previously shown that the induced level...... against A. salmonicida. The effect of immersion vaccination against A. salmonicida has been questioned over time. While some have presented excellent protection as a result of immersion vaccines, others have reported limited or absent protective effects. We have performed experiments on the protection...

  19. Polycation-decorated PLA microspheres induce robust immune responses via commonly used parenteral administration routes.

    Science.gov (United States)

    Chen, Xiaoming; Wang, Lianyan; Liu, Qi; Jia, Jilei; Liu, Yuan; Zhang, Weifeng; Ma, Guanghui; Su, Zhiguo

    2014-12-01

    Recombinant viral subunit-based vaccines have gained increasing attention due to their enhanced safety over the classic live-attenuated or inactivated vaccines. The low immunogenicity of the subunit antigen alone, however, requires the addition of an adjuvant to induce immunity. Particulate-based delivery systems have great potential for developing new vaccine adjuvants, compared to traditional aluminum-based saline adjuvants. The physicochemical properties of particulate vaccines have been extensively investigated; however, few studies have focused on how the administration route of various adjuvant-antigen combinations impacts the efficacy of the immune response. Here, for the first time, the viral Hepatitis B surface antigen (HBsAg) was combined with aluminum-based or cationic-microsphere (MP) based adjuvants to investigate the characteristics of immune responses elicited after immunization via the subcutaneous, intramuscular, or intraperitoneal routes respectively. In vitro, the MP-based vaccine significantly increased dendritic cell (DC) activation with up-regulated CD40 and CD80 expression and IL-12 production compared to alum-based vaccine. After immunization, both MP and alum-based vaccines produced increased IgG titers in mice. The administration route of these vaccines did influenced immune responses. The MP-based vaccine delivered via the intramuscular route yielded the highest levels of the IgG2a isotype. The alum-based vaccine, delivered via the same route, produced an IgG1-dominated humoral immune response. Moreover, subcutaneous and intramuscular immunizations with MP-based vaccine augmented Granzyme B, Th1-type cytokines (IL-2, IL-12, and IFN-γ), and Th2 cytokine IL-4 secretions. These results demonstrate that MP-based vaccines have the capacity to induce higher cellular and humoral immune response especially via an intramuscular administration route than an alum-based vaccine.

  20. Inducible defenses stay up late: temporal patterns of immune gene expression in Tenebrio molitor.

    Science.gov (United States)

    Johnston, Paul R; Makarova, Olga; Rolff, Jens

    2013-12-06

    The course of microbial infection in insects is shaped by a two-stage process of immune defense. Constitutive defenses, such as engulfment and melanization, act immediately and are followed by inducible defenses, archetypically the production of antimicrobial peptides, which eliminate or suppress the remaining microbes. By applying RNAseq across a 7-day time course, we sought to characterize the long-lasting immune response to bacterial challenge in the mealworm beetle Tenebrio molitor, a model for the biochemistry of insect immunity and persistent bacterial infection. By annotating a hybrid de novo assembly of RNAseq data, we were able to identify putative orthologs for the majority of components of the conserved insect immune system. Compared with Tribolium castaneum, the most closely related species with a reference genome sequence and a manually curated immune system annotation, the T. molitor immune gene count was lower, with lineage-specific expansions of genes encoding serine proteases and their countervailing inhibitors accounting for the majority of the deficit. Quantitative mapping of RNAseq reads to the reference assembly showed that expression of genes with predicted functions in cellular immunity, wound healing, melanization, and the production of reactive oxygen species was transiently induced immediately after immune challenge. In contrast, expression of genes encoding antimicrobial peptides or components of the Toll signaling pathway and iron sequestration response remained elevated for at least 7 days. Numerous genes involved in metabolism and nutrient storage were repressed, indicating a possible cost of immune induction. Strikingly, the expression of almost all antibacterial peptides followed the same pattern of long-lasting induction, regardless of their spectra of activity, signaling possible interactive roles in vivo. Copyright © 2014 Johnston et al.

  1. Hydralazine-induced pauci-immune glomerulonephritis: intriguing case series with misleading diagnoses

    Directory of Open Access Journals (Sweden)

    Faizan Babar

    2016-04-01

    Full Text Available Hydralazine has been used since the 1950s for the management of hypertension. Evidence for hydralazine-associated vasculitis dates to pre-ANCA (antineutrophil cytoplasmic antibodies era. This abstract describes two cases of ANCA-positive pauci-immune glomerulonephritis (GN in challenging scenarios where diagnosis was misconstrued. A comprehensive literature review was done to understand the pathogenesis of drug-induced pauci-immune GN. We have described key diagnostic features that are helpful in distinguishing idiopathic ANCA vasculitis from drug-induced vasculitis. Additionally, we have also described different treatments meant to provide therapy options with the least side effects.

  2. Surmounting tumor-induced immune suppression by frequent vaccination or immunization in the absence of B cells.

    Science.gov (United States)

    Oizumi, Satoshi; Deyev, Vadim; Yamazaki, Koichi; Schreiber, Taylor; Strbo, Natasa; Rosenblatt, Joseph; Podack, Eckhard R

    2008-05-01

    Tumor-induced immune suppression is one of the most difficult obstacles to the success of tumor immunotherapy. Here, we show that established tumors suppress CD8 T cell clonal expansion in vivo, which is normally observed in tumor-free mice upon antigen-specific glycoprotein (gp) 96-chaperone vaccination. Suppression of CD8 T-cell expansion by established tumors is independent of tumor-associated expression of the antigen that is recognized by the CD8-T-cell receptor. Vaccination of tumor-bearing mice is associated with increased cellular recruitment to the vaccine site compared with tumor-free mice. However, rejection of established, suppressive tumors required frequent (daily) gp96 vaccination. B cells are known to attenuate T helper cell-1 responses. We found that in B-cell deficient mice, tumor rejection of established tumors can be achieved by a single vaccination. Accordingly, in tumor-free B-cell deficient mice, cognate CD8 cytotoxic T lymphocyte clonal expansion is enhanced in response to gp96-chaperone vaccination. The data have implications for the study of tumor-induced immune suppression and for translation of tumor immunotherapy into the clinical setting. Frequent vaccination with cellular vaccines and concurrent B-cell depletion may greatly enhance the activity of anticancer vaccine therapy in patients.

  3. Study on enhancement anti-tumor effect of pEgr-hPTEN expression induced by ionizing radiation in vitro

    International Nuclear Information System (INIS)

    Tian Mei; Piao Chunji; Li Xiuyi; Yang Wei

    2005-01-01

    Objective: To investigate the effect of pEgr-hPTEN stable transfer combined with irradiation on the proliferation and apoptosis of SHG-44 human glioma cells in vitro. Methods; pEgr-hPTEN vector containing the exogenous wild type PTEn gene was transfected into SHG-44 cells under mediation of lipofectamine in vitro, positive cell clones were selected and amplified. Western blotting was used to detect the properties of PTEN expression induced by X-ray irradiation. Flow cytometry and cell growth curve were adopted to measure the effects of PTEN gene transfer combined with different doses of X-ray irradiation on cell proliferation and apoptosis of the transfected SHG-44 cells. Results: Expression of PTEN protein could be enhanced by X-ray irradiation in SHG-44-hPTEN stable transfer cells. PTEN protein relative level was in dose-dependent manner within 5 Gy. pEgr-hPTEN stable transfer combined with X-ray irradiation could significantly inhibit the proliferation and induce apoptosis of SHG-44 cells. At the 8th day after irradiation with different doses of X-ray, the numbers of SHG-44-hPTEN stable transfer cells were only 30.0%-50.0% of that of SHG-44-hPTEN/0 Gy group and 7.7%-13.0% of SHG-44/0 Gy group. The percentage of early apoptotic cells of SHG-44-hPTEN group after irradiation with X-ray irradiated were 1.5-2.3 times as much as that of SHG-44-hPTEN/0 Gy group, 1.9-4.4 times as much as that of SHG-44 irradiated group and 3.4-5.1 times as much as that of SHG-44/0 Gy group. Conclusion: The apoptosis of tumor cells could be significantly enhanced and its growth could be significantly inhibited by gene-radiotherapy in vitro. (authors)

  4. Nucleic acid-induced antiviral immunity in invertebrates: an evolutionary perspective.

    Science.gov (United States)

    Wang, Pei-Hui; Weng, Shao-Ping; He, Jian-Guo

    2015-02-01

    Nucleic acids derived from viral pathogens are typical pathogen associated molecular patterns (PAMPs). In mammals, the recognition of viral nucleic acids by pattern recognition receptors (PRRs), which include Toll-like receptors (TLRs) and retinoic acid-inducible gene (RIG)-I-like receptors (RLRs), induces the release of inflammatory cytokines and type I interferons (IFNs) through the activation of nuclear factor κB (NF-κB) and interferon regulatory factor (IRF) 3/7 pathways, triggering the host antiviral state. However, whether nucleic acids can induce similar antiviral immunity in invertebrates remains ambiguous. Several studies have reported that nucleic acid mimics, especially dsRNA mimic poly(I:C), can strongly induce non-specific antiviral immune responses in insects, shrimp, and oyster. This behavior shows multiple similarities to the hallmarks of mammalian IFN responses. In this review, we highlight the current understanding of nucleic acid-induced antiviral immunity in invertebrates. We also discuss the potential recognition and regulatory mechanisms that confer non-specific antiviral immunity on invertebrate hosts. Copyright © 2014 Elsevier Ltd. All rights reserved.

  5. Acute symptomatic hypocalcemia from immune checkpoint therapy-induced hypoparathyroidism.

    Science.gov (United States)

    Win, Myint Aung; Thein, Kyaw Zin; Qdaisat, Aiham; Yeung, Sai-Ching Jim

    2017-07-01

    Ipilimumab (a monoclonal antibody against CTLA-4) and nivolumab (a humanized antibody against PD-1) target these immune checkpoint pathways and are used for treatment of melanoma and an increasing number of other cancers. However, they may cause immune-related adverse effects (IRAEs). Although many endocrinopathies are known to be IRAEs, primary hypoparathyroidism with severe hypocalcemia has never been reported. This is the first case of hypoparathyroidism as an IRAE presenting to an Emergency Department with acute hypocalcemia. A 73-year-old man with metastatic melanoma presented to the Emergency Department for the chief complaints of imbalance, general muscle weakness, abdominal pain and tingling in extremities. He had wide spread metastasis, and begun immunotherapy with concurrent ipilimumab and nivolumab 1.5months ago. At presentation, he had ataxia, paresthesia in the hands and feet, and abdominal cramping. Magnetic resonance imaging of the brain was unremarkable. He was found to be hypocalcemic with undetectable plasma parathyroid hormone. He was admitted for treatment of symptomatic hypocalcemia and was diagnosed with primary hypoparathyroidism. Shortly afterwards, he had thyrotoxicosis manifesting as tachycardia and anxiety, followed by development of primary hypothyroidism. At 4months after the Emergency Department visit, his parathyroid function and thyroid function had not recovered, and required continued thyroid hormone replacement and calcium and vitamin D treatment for hypocalcemia. Primary hypoparathyroidism caused by ipilimumab and nivolumab may acute manifest with severe symptomatic hypocalcemia. Emergency care providers should be aware of hypoparathyroidism as a new IRAE in this new era of immuno-oncology. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Micelles of zinc protoporphyrin conjugated to N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer for imaging and light-induced antitumor effects in vivo.

    Science.gov (United States)

    Nakamura, Hideaki; Liao, Long; Hitaka, Yuki; Tsukigawa, Kenji; Subr, Vladimir; Fang, Jun; Ulbrich, Karel; Maeda, Hiroshi

    2013-02-10

    We synthesized N-(2-hydroxypropyl)methacrylamide polymer conjugated with zinc protoporphyrin (HPMA-ZnPP) and evaluated its application for tumor detection by imaging and treatment by light exposure using in mouse sarcoma model. To characterize HPMA-ZnPP micelle, we measured its micellar size, surface charge, stability, photochemical, biochemical properties and tissue distribution. In vivo anti-tumor effect and fluorescence imaging were carried out to validate the tumor selective accumulation and therapeutic effect by inducing singlet oxygen by light exposure. HPMA-ZnPP was highly water soluble and formed micelles spontaneously having hydrophobic clustered head group of ZnPP, in aqueous solution, with a hydrodynamic diameter of 82.8±41.8 nm and zeta-potential of +1.12 mV. HPMA-ZnPP had a long plasma half-life and effectively and selectively accumulated in tumors. Although HPMA-ZnPP alone had no toxicity in S-180 tumor-bearing mice, light-irradiation significantly suppressed tumor growth in vivo, similar to the cytotoxicity to HeLa cells in vitro upon endoscopic light-irradiation. HPMA-ZnPP can visualize tumors by fluorescence after i.v. injection, which suggests that this micelle may be useful for both tumor imaging and therapy. Here we describe preparation of a new fluorescence nanoprobe that is useful for simultaneous tumor imaging and treatment, and application to fluorescence endoscopy is now at visible distance. Copyright © 2012 Elsevier B.V. All rights reserved.

  7. Macrophage Inducible C-Type Lectin As a Multifunctional Player in Immunity

    Directory of Open Access Journals (Sweden)

    Emmanuel C. Patin

    2017-07-01

    Full Text Available The macrophage-inducible C-type lectin (Mincle is an innate immune receptor on myeloid cells sensing diverse entities including pathogens and damaged cells. Mincle was first described as a receptor for the mycobacterial cell wall glycolipid, trehalose-6,6′-dimycolate, or cord factor, and the mammalian necrotic cell-derived alarmin histone deacetylase complex unit Sin3-associated protein 130. Upon engagement by its ligands, Mincle induces secretion of innate cytokines and other immune mediators modulating inflammation and immunity. Since its discovery more than 25 years ago, the understanding of Mincle’s immune function has made significant advances in recent years. In addition to mediating immune responses to infectious agents, Mincle has been linked to promote tumor progression, autoimmunity, and sterile inflammation; however, further studies are required to completely unravel the complex role of Mincle in these distinct host responses. In this review, we discuss recent findings on Mincle’s biology with an emphasis on its diverse functions in immunity.

  8. A novel colchicine-based microtubule inhibitor exhibits potent antitumor activity by inducing mitochondrial mediated apoptosis in MIA PaCa-2 pancreatic cancer cells.

    Science.gov (United States)

    Kumar, Ashok; Singh, Baljinder; Mahajan, Girish; Sharma, Parduman R; Bharate, Sandip B; Mintoo, Mubashir J; Mondhe, Dilip M

    2016-10-01

    Colchicine, an antimitotic alkaloid isolated from Colchicum autumnale, is a classical drug for treatment of gout and familial Mediterranean fever. It causes antiproliferative effects through the inhibition of microtubule formation, which leads to mitotic arrest and cell death by apoptosis. Here, we report that a novel colchicine analog, 4o (N-[(7S)-1,2,3-trimethoxy-9-oxo-10-[3-(trifluoromethyl)-4-chlorophenylamino]-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl]acetamide), which exhibited potent anticancer activities both in vitro and in vivo. In this study, 4o with excellent pharmacokinetic profile and no P-gp induction liability displayed strong inhibition of proliferation against various human cancer cell lines. However, pancreatic cancer cell line MIA PaCa-2 was found to be more sensitive towards 4o and showed strong inhibition in concentration and time-dependent manner. By increasing intracellular reactive oxygen species (ROS) levels, 4o induced endoplasmic reticular stress and mitochondrial dysfunction in MIA PaCa-2 cells. Blockage of ROS production reversed 4o-induced endoplasmic reticulum (ER) stress, calcium release, and cell death. More importantly, it revealed that increased ROS generation might be an effective strategy in treating human pancreatic cancer. Further 4o treatment induced mitotic arrest, altered the expression of cell cycle-associated proteins, and disrupted the microtubules in MIA PaCa-2 cells. 4o treatment caused loss of mitochondrial membrane potential, cytochrome c release, upregulation of Bax, downregulation of Bcl-2, and cleavage of caspase-3, thereby showing activation of mitochondrial mediated apoptosis. The in vivo anticancer activity of the compound was studied using sarcoma-180 (ascitic) and leukemia (P388 lymphocytic and L1210 lymphoid) models in mice and showed promising antitumor activity with the least toxicity unlike colchicine. Such studies have hitherto not been reported. Taken together, these findings highlighted that 4o, a

  9. Increased accumulation of hypoxia-inducible factor-1α with reduced transcriptional activity mediates the antitumor effect of triptolide

    Directory of Open Access Journals (Sweden)

    Li Zheng

    2010-10-01

    Full Text Available Abstract Background Hypoxia-inducible factor-1α (HIF-1α, a critical transcription factor to reduced O2 availability, has been demonstrated to be extensively involved in tumor survival, aggressive progression, drug resistance and angiogenesis. Thus it has been considered as a potential anticancer target. Triptolide is the main principle responsible for the biological activities of the Traditional Chinese Medicine tripterygium wilfordii Hook F. Triptolide possesses great chemotherapy potential for cancer with its broad-spectrum anticancer, antiangiogenesis, and drug-resistance circumvention activities. Numerous biological molecules inhibited by triptolide have been viewed as its possible targets. However, the anticancer action mechanisms of triptolide remains to be further investigated. Here we used human ovarian SKOV-3 cancer cells as a model to probe the effect of triptolide on HIF-1α. Results Triptolide was observed to inhibit the proliferation of SKOV-3 cells, and meanwhile, to enhance the accumulation of HIF-1α protein in SKOV-3, A549 and DU145 cells under different conditions. Triptolide did not change the kinetics or nuclear localization of HIF-1α protein or the 26 S proteasome activity in SKOV-3 cells. However, triptolide was found to increase the levels of HIF-1α mRNA. Unexpectedly, the HIF-1α protein induced by triptolide appeared to lose its transcriptional activity, as evidenced by the decreased mRNA levels of its target genes including VEGF, BNIP3 and CAIX. The results were further strengthened by the lowered secretion of VEGF protein, the reduced sprout outgrowth from the rat aorta rings and the inhibitory expression of the hypoxia responsive element-driven luciferase reporter gene. Moreover, the silencing of HIF-1α partially prevented the cytotoxicity and apoptosis triggered by triptolide. Conclusions The potent induction of HIF-1α protein involved in its cytotoxicity, together with the suppression of HIF-1 transcriptional

  10. Virus-associated activation of innate immunity induces rapid disruption of Peyer's patches in mice.

    Science.gov (United States)

    Heidegger, Simon; Anz, David; Stephan, Nicolas; Bohn, Bernadette; Herbst, Tina; Fendler, Wolfgang Peter; Suhartha, Nina; Sandholzer, Nadja; Kobold, Sebastian; Hotz, Christian; Eisenächer, Katharina; Radtke-Schuller, Susanne; Endres, Stefan; Bourquin, Carole

    2013-10-10

    Early in the course of infection, detection of pathogen-associated molecular patterns by innate immune receptors can shape the subsequent adaptive immune response. Here we investigate the influence of virus-associated innate immune activation on lymphocyte distribution in secondary lymphoid organs. We show for the first time that virus infection of mice induces rapid disruption of the Peyer's patches but not of other secondary lymphoid organs. The observed effect was not dependent on an active infectious process, but due to innate immune activation and could be mimicked by virus-associated molecular patterns such as the synthetic double-stranded RNA poly(I:C). Profound histomorphologic changes in Peyer's patches were associated with depletion of organ cellularity, most prominent among the B-cell subset. We demonstrate that the disruption is entirely dependent on type I interferon (IFN). At the cellular level, we show that virus-associated immune activation by IFN-α blocks B-cell trafficking to the Peyer's patches by downregulating expression of the homing molecule α4β7-integrin. In summary, our data identify a mechanism that results in type I IFN-dependent rapid but reversible disruption of intestinal lymphoid organs during systemic viral immune activation. We propose that such rerouted lymphocyte trafficking may impact the development of B-cell immunity to systemic viral pathogens.

  11. Native and aspirin-triggered lipoxins control innate immunity by inducing proteasomal degradation of TRAF6.

    Science.gov (United States)

    Machado, Fabiana S; Esper, Lísia; Dias, Alexandra; Madan, Rajat; Gu, YuanYuan; Hildeman, David; Serhan, Charles N; Karp, Christopher L; Aliberti, Júlio

    2008-05-12

    Innate immune signaling is critical for the development of protective immunity. Such signaling is, perforce, tightly controlled. Lipoxins (LXs) are eicosanoid mediators that play key counterregulatory roles during infection. The molecular mechanisms underlying LX-mediated control of innate immune signaling are of interest. In this study, we show that LX and aspirin (ASA)-triggered LX (ATL) inhibit innate immune signaling by inducing suppressor of cytokine signaling (SOCS) 2-dependent ubiquitinylation and proteasome-mediated degradation of TNF receptor-associated factor (TRAF) 2 and TRAF6, which are adaptor molecules that couple TNF and interleukin-1 receptor/Toll-like receptor family members to intracellular signaling events. LX-mediated degradation of TRAF6 inhibits proinflammatory cytokine production by dendritic cells. This restraint of innate immune signaling can be ablated by inhibition of proteasome function. In vivo, this leads to dysregulated immune responses, accompanied by increased mortality during infection. Proteasomal degradation of TRAF6 is a central mechanism underlying LX-driven immune counterregulation, and a hitherto unappreciated mechanism of action of ASA. These findings suggest a new molecular target for drug development for diseases marked by dysregulated inflammatory responses.

  12. Protein-Free Hapten-Carbon Nanotube Constructs Induce the Secondary Immune Response.

    Science.gov (United States)

    Ceballos-Alcantarilla, Eric; Abad-Somovilla, Antonio; Agulló, Consuelo; Abad-Fuentes, Antonio; Mercader, Josep V

    2017-06-21

    Carbon nanotubes are novel technological tools with multiple applications. The interaction between such nanoparticles and living organisms is nowadays a matter of keen research by academic and private institutions. In this study, carbon nanotube constructs were investigated as delivery vehicles for immunostimulation and induction of the secondary immune response to a small organic molecule, namely, a hapten. Two types of nanoconstructs were prepared: on one hand, carbon nanotubes carrying a protein bioconjugate of a hapten covalently linked to the carbon surface, and on the other hand, covalent carbon nanotube constructs of the same model chemical compound without the carrier protein. Nanotube vehicles carrying a hapten-protein bioconjugate were demonstrated to stimulate the immune system and to induce a strong primary immune response against the hapten with as low as 0.1 μg of the model chemical. The influence of the different elements of those nanoconstructs over the immune response was investigated to better understand the molecular mechanisms that are involved. As expected, the presence of the carrier protein was shown to be necessary in order to trigger the immune response. Interestingly, we found that a remarkable secondary immune response to the model organic compound occurred in the absence of a carrier protein. Additionally, a satisfactory adjuvant effect of carbon nanotubes was observed and a potent immune response was elicited without employing an oil-based adjuvant.

  13. A trypsin inhibitor from rambutan seeds with antitumor, anti-HIV-1 reverse transcriptase, and nitric oxide-inducing properties.

    Science.gov (United States)

    Fang, Evandro Fei; Ng, Tzi Bun

    2015-04-01

    Nephelium lappaceum L., commonly known as "rambutan," is a typical tropical tree and is well known for its juicy and sweet fruit which has an exotic flavor. Chemical studies on rambutan have led to the identification of various components such as monoterpene lactones and volatile compounds. Here, a 22.5-kDa trypsin inhibitor (N . lappaceum trypsin inhibitor (NLTI)) was isolated from fresh rambutan seeds using liquid chromatographical techniques. NLTI reduced the proteolytic activities of both trypsin and α-chymotrypsin. Dithiothreitol reduced the trypsin inhibitory activity of NLTI at a concentration of 1 mM, indicating that an intact disulfide bond is essential to the activity. NLTI inhibited HIV-1 reverse transcriptase with an IC50 of 0.73 μM. In addition, NLTI manifested a time- and dose-dependent inhibitory effect on growth in many tumor cells. NLTI is one of the few trypsin inhibitors with nitric oxide-inducing activity and may find application in tumor therapy.

  14. Intranasal immunization with novel EspA-Tir-M fusion protein induces protective immunity against enterohemorrhagic Escherichia coli O157:H7 challenge in mice.

    Science.gov (United States)

    Lin, Ruqin; Zhu, Bo; Zhang, Yiduo; Bai, Yang; Zhi, Fachao; Long, Beiguo; Li, Yawen; Wu, Yuhua; Wu, Xianbo; Fan, Hongying

    2017-04-01

    Enterohemorrhagic Escherichia coli (EHEC) O157:H7 causes hemorrhagic colitis and hemolytic uremic syndrome in humans. Due to the risks associated with antibiotic treatment against EHEC O157:H7 infection, vaccines represent a promising method for prevention of EHEC O157:H7 infection. Therefore, we constructed the novel bivalent antigen EspA-Tir-M as a candidate EHEC O157:H7 subunit vaccine. We then evaluated the immunogenicity of this novel EHEC O157:H7 subunit vaccine. Immune responses to the fusion protein administered by intranasal and subcutaneous routes were compared in mice. Results showed higher levels of specific mucosal and systemic antibody responses induced by intranasal as compared to subcutaneous immunization. Intranasal immunization enhanced the concentration of interleukin-4, interleukin-10, and interferon-γ, while subcutaneous immunization enhanced only the latter two. In addition, intranasal immunization protected against EHEC O157:H7 colonization and infection in mice at a rate of 90%.Histopathological analysis revealed that vaccination reduced colon damage, especially when administered intranasally. In contrast, subcutaneous immunization elicited a weak immune response and exhibited a low protection rate. These findings demonstrate that intranasal immunization with the fusion protein induces both humoral and cellular immune (Th1/Th2) responses in mice. The novel EspA-Tir-M novel fusion protein therefore represents a promising subunit vaccine against EHEC O157:H7 infection. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Intranasal immunization with influenza VLPs incorporating membrane-anchored flagellin induces strong heterosubtypic protection.

    Directory of Open Access Journals (Sweden)

    Bao-Zhong Wang

    2010-11-01

    Full Text Available We demonstrated previously that the incorporation of a membrane-anchored form of flagellin into influenza virus-like particles (VLPs improved the immunogenicity of VLPs significantly, inducing partially protective heterosubtypic immunity by intramuscular immunization. Because the efficacy of mucosal vaccination is highly dependent on an adjuvant, and is particularly effective for preventing mucosal infections such as influenza, we determined whether the membrane-anchored flagellin is an efficient adjuvant for VLP vaccines by a mucosal immunization route. We compared the adjuvant effect of membrane-anchored and soluble flagellins for immunization with influenza A/PR8 (H1N1 VLPs by the intranasal route in a mouse model. The results demonstrate that membrane-anchored flagellin is an effective adjuvant for intranasal (IN immunization, inducing enhanced systemic and mucosal antibody responses. High cellular responses were also observed as shown by cytokine production in splenocyte cultures when stimulated with viral antigens. All mice immunized with flagellin-containing VLPs survived challenge with a high lethal dose of homologous virus as well as a high dose heterosubtypic virus challenge (40 LD(50 of A/Philippines/82, H3N2. In contrast, no protection was observed with a standard HA/M1 VLP group upon heterosubtypic challenge. Soluble flagellin exhibited a moderate adjuvant effect when co-administered with VLPs by the mucosal route, as indicated by enhanced systemic and mucosal responses and partial heterosubtypic protection. The membrane-anchored form of flagellin incorporated together with antigen into influenza VLPs is effective as an adjuvant by the mucosal route and unlike standard VLPs, immunization with such chimeric VLPs elicits protective immunity to challenge with a distantly related influenza A virus.

  16. Preclinical Evidence of Anti-Tumor Activity Induced by EZH2 Inhibition in Human Models of Synovial Sarcoma.

    Directory of Open Access Journals (Sweden)

    Satoshi Kawano

    Full Text Available The catalytic activities of covalent and ATP-dependent chromatin remodeling are central to regulating the conformational state of chromatin and the resultant transcriptional output. The enzymes that catalyze these activities are often contained within multiprotein complexes in nature. Two such multiprotein complexes, the polycomb repressive complex 2 (PRC2 methyltransferase and the SWItch/Sucrose Non-Fermentable (SWI/SNF chromatin remodeler have been reported to act in opposition to each other during development and homeostasis. An imbalance in their activities induced by mutations/deletions in complex members (e.g. SMARCB1 has been suggested to be a pathogenic mechanism in certain human cancers. Here we show that preclinical models of synovial sarcoma-a cancer characterized by functional SMARCB1 loss via its displacement from the SWI/SNF complex through the pathognomonic SS18-SSX fusion protein-display sensitivity to pharmacologic inhibition of EZH2, the catalytic subunit of PRC2. Treatment with tazemetostat, a clinical-stage, selective and orally bioavailable small-molecule inhibitor of EZH2 enzymatic activity reverses a subset of synovial sarcoma gene expression and results in concentration-dependent cell growth inhibition and cell death specifically in SS18-SSX fusion-positive cells in vitro. Treatment of mice bearing either a cell line or two patient-derived xenograft models of synovial sarcoma leads to dose-dependent tumor growth inhibition with correlative inhibition of trimethylation levels of the EZH2-specific substrate, lysine 27 on histone H3. These data demonstrate a dependency of SS18-SSX-positive, SMARCB1-deficient synovial sarcomas on EZH2 enzymatic activity and suggests the potential utility of EZH2-targeted drugs in these genetically defined cancers.

  17. Perillyl alcohol suppresses antigen-induced immune responses in the lung

    Energy Technology Data Exchange (ETDEWEB)

    Imamura, Mitsuru; Sasaki, Oh; Okunishi, Katsuhide; Nakagome, Kazuyuki; Harada, Hiroaki; Kawahata, Kimito; Tanaka, Ryoichi; Yamamoto, Kazuhiko [Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo (Japan); Dohi, Makoto, E-mail: mdohi-tky@umin.ac.jp [Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo (Japan); Institute of Respiratory Immunology, Shibuya Clinic for Respiratory Diseases and Allergology, Tokyo (Japan)

    2014-01-03

    Highlights: •Perillyl alcohol (POH) is an isoprenoid which inhibits the mevalonate pathway. •We examined whether POH suppresses immune responses with a mouse model of asthma. •POH treatment during sensitization suppressed Ag-induced priming of CD4{sup +} T cells. •POH suppressed airway eosinophila and cytokine production in thoracic lymph nodes. -- Abstract: Perillyl alcohol (POH) is an isoprenoid which inhibits farnesyl transferase and geranylgeranyl transferase, key enzymes that induce conformational and functional changes in small G proteins to conduct signal production for cell proliferation. Thus, it has been tried for the treatment of cancers. However, although it affects the proliferation of immunocytes, its influence on immune responses has been examined in only a few studies. Notably, its effect on antigen-induced immune responses has not been studied. In this study, we examined whether POH suppresses Ag-induced immune responses with a mouse model of allergic airway inflammation. POH treatment of sensitized mice suppressed proliferation and cytokine production in Ag-stimulated spleen cells or CD4{sup +} T cells. Further, sensitized mice received aerosolized OVA to induce allergic airway inflammation, and some mice received POH treatment. POH significantly suppressed indicators of allergic airway inflammation such as airway eosinophilia. Cytokine production in thoracic lymph nodes was also significantly suppressed. These results demonstrate that POH suppresses antigen-induced immune responses in the lung. Considering that it exists naturally, POH could be a novel preventive or therapeutic option for immunologic lung disorders such as asthma with minimal side effects.

  18. Steroid-induced femoral head osteonecrosis in immune thrombocytopenia treatment with osteochondral autograft transplantation.

    Science.gov (United States)

    Fotopoulos, Vasileios Ch; Mouzopoulos, George; Floros, Themistoklis; Tzurbakis, Matthaios

    2015-09-01

    Osteonecrosis of the femoral head is a devastating complication of steroid administration and has rarely been observed in the treatment of immune thrombocytopenia. The treatment of osteochondral defects in advanced stages of avascular necrosis (AVN), characterized by collapse of the subchondral bone, remains an unsolved burden in orthopedic surgery. In this report, we present a case of a 19-year-old female that was admitted in the Emergency Department with walking disability and painful hip joint movement due to steroid-induced femoral head osteonecrosis. Two years before she was diagnosed with immune thrombocytopenia, for which she received pulse steroid therapy with high dose of dexamethasone and underwent a splenectomy. This case report is the first to describe the use of osteochondral autograft transplantation as a treatment of steroid-induced AVN of the femoral head due to immune thrombocytopenia at the age of 19 years with very good clinical and radiological results 3 years postoperatively.

  19. Vitamin A induces inhibitory histone methylation modifications and down-regulates trained immunity in human monocytes

    DEFF Research Database (Denmark)

    Arts, Rob J W; Blok, Bastiaan A; van Crevel, Reinout

    2015-01-01

    Epidemiologic studies suggest that VAS has long-lasting immunomodulatory effects. We hypothesized that ATRA inhibits inflammatory cytokines in a model of trained immunity in monocytes by inducing epigenetic reprogramming through histone modifications. We used an previously described in vitro model...... of trained immunity, in which adherent monocytes of healthy volunteers were incubated for 24 h with BCG in the presence or absence of ATRA. After washing the cells, they were incubated for an additional 6 d in culture medium and restimulated with microbial ligands, and cytokine production was assessed. ATRA...... cytokine production. In addition to H3K9me3, the stimulatory histone mark H3K4me3 was down-regulated by ATRA at several promoter locations of cytokine genes. Therefore, we can conclude that ATRA inhibits cytokine production in models of direct stimulation or BCG-induced trained immunity...

  20. Nickel-induced hypersensitivity: etiology, immune reactions, prevention and therapy.

    Science.gov (United States)

    Hostýnek, Jurij J

    2002-08-01

    As a contact allergen causing type I and type IV hypersensitivity, mediated by reagins and allergen-specific T lymphocytes, expressed in a wide range of cutaneous eruptions following dermal or systemic exposure, nickel has acquired the distinction of being among the most frequent causes of hypersensitivity, occupationally as well as among the general population. In synoptic form the many effects that nickel has on the organism are presented, to provide a comprehensive picture of the aspects of that metal with many biologically noxious, but metallurgically indispensable characteristics. This paper reviews the epidemiology, the prognosis for occupational and non-occupational nickel allergic hypersensitivity (NAH), the many types of exposure and the resulting immune responses, immunotoxicity and rate of diffusion through the skin. Alternatives towards prevention and remediation, topical and systemic, for this pervasive and increasing form of morbidity resulting from multiple types of exposure are discussed. Merits and limitations of preventive measures in industry and private life are considered, as well as the effectiveness of topical and systemic therapy in treating NAH.

  1. DAMP signaling is a key pathway inducing immune modulation after brain injury.

    Science.gov (United States)

    Liesz, Arthur; Dalpke, Alexander; Mracsko, Eva; Antoine, Daniel J; Roth, Stefan; Zhou, Wei; Yang, Huan; Na, Shin-Young; Akhisaroglu, Mustafa; Fleming, Thomas; Eigenbrod, Tatjana; Nawroth, Peter P; Tracey, Kevin J; Veltkamp, Roland

    2015-01-14

    Acute brain lesions induce profound alterations of the peripheral immune response comprising the opposing phenomena of early immune activation and subsequent immunosuppression. The mechanisms underlying this brain-immune signaling are largely unknown. We used animal models for experimental brain ischemia as a paradigm of acute brain lesions and additionally investigated a large cohort of stroke patients. We analyzed release of HMGB1 isoforms by mass spectrometry and investigated its inflammatory potency and signaling pathways by immunological in vivo and in vitro techniques. Features of the complex behavioral sickness behavior syndrome were characterized by homecage behavior analysis. HMGB1 downstream signaling, particularly with RAGE, was studied in various transgenic animal models and by pharmacological blockade. Our results indicate that the cytokine-inducing, fully reduced isoform of HMGB1 was released from the ischemic brain in the hyperacute phase of stroke in mice and patients. Cytokines secreted in the periphery in response to brain injury induced sickness behavior, which could be abrogated by inhibition of the HMGB1-RAGE pathway or direct cytokine neutralization. Subsequently, HMGB1-release induced bone marrow egress and splenic proliferation of bone marrow-derived suppressor cells, inhibiting the adaptive immune responses in vivo and vitro. Furthermore, HMGB1-RAGE signaling resulted in functional exhaustion of mature monocytes and lymphopenia, the hallmarks of immune suppression after extensive ischemia. This study introduces the HMGB1-RAGE-mediated pathway as a key mechanism explaining the complex postischemic brain-immune interactions. Copyright © 2015 the authors 0270-6474/15/350583-16$15.00/0.

  2. Does exposure to UV radiation induce a shift to a Th-2-like immune reaction?

    International Nuclear Information System (INIS)

    Ullrich, S.E.

    1996-01-01

    In addition to being the primary cause of skin cancer, UV radiation is immune suppressive and there appears to be a link between the ability of UV to suppress the immune response and induce skin cancer. Cytokines made by UV-irradiated keratinocytes play an essential role in activating immune suppression. In particular, we have found that keratinocyte-derived interleukin (IL)-10 is responsible for the systemic impairment of antigen presenting cell function and the UV-induced suppression of delayed-type hypersenstivity (DTH). Antigen presentation by splenic adherent cells isolated from UV-irradiated mice to T helper-1 type T (Th1) cells is suppressed, whereas antigen presentation to T helper-2 type T (Th2) cells is enhanced. The enhanced antigen presentation to Th2 cells and the impaired presentation to Th1 cells can be reversed in vivo by injecting the UV-irradiated mice with monoclonal anti-IL-10 antibody. Furthermore, immune suppression can be transferred from UV-irradiated mice to normal recipients by adoptive transfer of T cells. Injecting the recipient mice with anti-IL-4 or anti-IL-10 prevents the transfer of immune suppression, suggesting the suppressor cells are Th2 cells. In addition, injecting UV-irradiated mice with IL-12, a cytokine that has been shown to be the primary inducer of Th1 cells, and one that prevents the differentiation of Th2 cells in vivo, reverses UV-induced immune suppression. These findings support the hypothesis that UV exposure activates IL-10 secretion, which depresses the function of Th1 cells, while enhancing the activity of Th2 cells. (Author)

  3. Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens

    Science.gov (United States)

    Under physiological conditions the gut-associated lymphoid tissues not only prevent the induction of a local inflammatory immune response, but also induce systemic tolerance to fed antigens. A notable exception is coeliac disease, where genetically susceptible individuals expressing human leukocyte...

  4. Effect of plasmapheresis on the immune system in endotoxin-induced sepsis

    DEFF Research Database (Denmark)

    Toft, P; Schmidt, R; Broechner, A C

    2008-01-01

    BACKGROUND: It has been proposed that plasmapheresis is most effective when applied early in Gram-negative sepsis. We therefore studied the effect of early plasmapheresis on immunity in experimental Escherichia coli endotoxin-induced sepsis. METHODS: 20 pigs received 30 microg/kg of E. coli...

  5. [Immune system and tumors].

    Science.gov (United States)

    Terme, Magali; Tanchot, Corinne

    2017-02-01

    Despite having been much debated, it is now well established that the immune system plays an essential role in the fight against cancer. In this article, we will highlight the implication of the immune system in the control of tumor growth and describe the major components of the immune system involved in the antitumoral immune response. The immune system, while exerting pressure on tumor cells, also will play a pro-tumoral role by sculpting the immunogenicity of tumors cells as they develop. Finally, we will illustrate the numerous mechanisms of immune suppression that take place within the tumoral microenvironment which allow tumor cells to escape control from the immune system. The increasingly precise knowledge of the brakes to an effective antitumor immune response allows the development of immunotherapy strategies more and more innovating and promising of hope. Copyright © 2016. Published by Elsevier Masson SAS.

  6. Assessment of in vivo anti-tumor activity of human umbilical vein endothelial cell vaccines prepared by various antigen forms.

    Science.gov (United States)

    Zhou, Ling; Si, Chunfeng; Li, Defang; Lu, Meiyu; Zhong, Weilan; Xie, Zeping; Guo, Lin; Zhang, Shumin; Xu, Maolei

    2018-03-01

    Human umbilical vein endothelial cell (HUVEC) vaccine has been proved as an effective whole-cell vaccine, but the modest therapeutic anti-tumor efficiency limits its clinical use. Various antigen forms, including paraformaldehyde-fixed HUVEC, glutaraldehyde-fixed HUVEC, HUVEC lysate and live HUVEC, have been intensively used in HUVEC vaccine preparation, however, the most effective antigen form has not yet been identified. In the present study, these four commonly used antigen forms were used to prepare vaccines named Para-Fixed-EC, Glu-Fixed-EC, Lysate-EC, and Live-EC respectively, and the anti-tumor efficacy of these four vaccines was investigated. Results showed that Live-EC exhibited the most favorable anti-tumor growth and metastasis effects among the four vaccines in both H22 hepatocellular carcinoma and Lewis lung cancer models. High titer anti-HUVEC antibodies were detected in Live-EC immunized mice sera, and the immune sera of Live-EC group could significantly inhibit HUVEC proliferation and tube formation. Moreover, T cells isolated from Live-EC immunized mice exhibited strong cytotoxicity against HUVEC cells, with an increasing IFN-γ and decreasing Treg production in Live-EC immunized mice. Finally, CD31 immunohistochemical analysis of the excised tumors verified a significant reduction in vessel density after Live-EC vaccination, which was in accordance with the anti-tumor efficiency. Taken together, all the results proved that live HUVEC was the most effective antigen form to induce robust HUVEC specific antibody and CTL responses, which could lead to the significant inhibition of tumor growth and metastasis. We hope the present findings would provide a rationale for the further optimization of HUVEC vaccine. Copyright © 2017. Published by Elsevier B.V.

  7. Bacteriophages support anti-tumor response initiated by DC-based vaccine against murine transplantable colon carcinoma.

    Science.gov (United States)

    Pajtasz-Piasecka, Elzbieta; Rossowska, Joanna; Duś, Danuta; Weber-Dabrowska, Beata; Zabłocka, Agnieszka; Górski, Andrzej

    2008-02-15

    Bacteriophages in eukaryotic hosts may behave as particulate antigens able to activate the innate immune system and generate adaptive immunity. Dendritic cells (DCs) play a key role in the initiation of the immune response, mainly by priming T cell-mediated immunity. For this reason, they are increasingly applied as an adjuvant for effective anti-tumor therapies in animal models as well as in a few clinical trials. The presented study focused on the application of mouse DCs which were activated with T4 bacteriophages (T4 phages, T4) and further loaded with tumor antigens (TAg) in inducing an anti-tumor response. The activation of bone marrow-derived DCs with T4 phages and TAg resulted in augmentation of their differentiation marker expression accompanied by an enhanced ability to prime T cells for IFN-gamma production. These activated DCs (BM-DC/T4+TAg) were used in experimental immunotherapy of C57BL/6 mice bearing advanced MC38 colon carcinoma tumors. As a result of their triple application, a significant tumor growth delay, up to 19 days, was observed compared with the controls - treated with BM-DCs activated only with T4 phages, TAg, or lipopolysaccharide solution ["solvent"], where the tumor growth delay did not exceed 7 days. The percentage of tumor growth inhibition estimated 10 days after the third cell injection ranged from 32% (for animals treated with BM-DC/TAg cells) to 76% (for animals treated with BM-DC/T4+TAg cells) over the tumor-bearing untreated control mice. The obtained data indicate that in vitro interactions between T4 phages and BM-DCs followed by TAg activation caused augmentation of the anti-tumor effect when DCs were used as a vaccine for tumor-bearing mice treatment. Therefore, pretreatment of DCs with the phages may be considered as a beneficial element of a novel strategy in anti-tumor immunotherapy.

  8. The radiosensitizing effect of immunoadjuvant OM-174 requires cooperation between immune and tumor cells through interferon-gamma and inducible nitric oxide synthase

    International Nuclear Information System (INIS)

    Ridder, Mark de; Verovski, Valeri N.; Chiavaroli, Carlo; Berge, Dirk L. van den; Monsaert, Christinne; Law, Kalun; Storme, Guy A.

    2006-01-01

    Purpose: To explore whether antitumor immunoadjuvant OM-174 can stimulate immune cells to produce interferon-γ (IFN-γ) and thereby radiosensitize tumor cells. Methods and Materials: Splenocytes from BALB/c mice were stimulated by OM-174 at plasma-achievable concentrations (0.03-3 μg/mL), and afterward analyzed for the expression and secretion of IFN-γ by reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Stimulated splenocytes were used as a source of IFN-γ to radiosensitize hypoxic EMT-6 tumor cells through the cytokine-inducible isoform of nitric oxide synthase (iNOS). Results: OM-174 activated the production of IFN-γ at high levels that reached 70 ng/mL in normoxia (21% oxygen) and 27 ng/mL in tumor-relevant hypoxia (1% oxygen). This caused up to 2.1-fold radiosensitization of EMT-6 tumor cells, which was associated with the iNOS-mediated production of the radiosensitizing molecule nitric oxide, as confirmed by accumulation of its oxidative metabolite nitrite, Western blot analysis, and reverse transcriptase-polymerase chain reaction. Both iNOS activation and radiosensitization were counteracted by neutralizing antibodies against IFN-γ. The same mechanism of radiosensitization through the IFN-γ secretion pathway was identified for IL-12 + IL-18, which are known to mediate IFN-γ responses. Hypoxia displayed a dual effect on the immune-tumor cell interaction, by downregulating the expression of the IFN-γ gene while upregulating iNOS at transcriptional level. Conclusion: Immunoadjuvant OM-174 is an efficient radiosensitizer of tumor cells through activation of the IFN-γ secretion pathway in immune cells. This finding indicates a rationale for combining immunostimulatory and radiosensitizing strategies and extends the potential therapeutic applications of OM-174

  9. Lipopolysaccharide induces immune activation and SIV replication in rhesus macaques of Chinese origin.

    Directory of Open Access Journals (Sweden)

    Rong Bao

    Full Text Available BACKGROUND: Chronic immune activation is a hallmark of progressive HIV infection and a key determinant of immunodeficiency in HIV-infected individuals. Bacterial lipopolysaccharide (LPS in the circulation has been implicated as a key factor in HIV infection-related systemic immune activation. We thus investigate the impact of LPS on systemic immune activation in simian immunodeficiency virus (SIV-infected rhesus macaques of Chinese origin. METHODS: The animals were inoculated intravenously with SIVmac239. The levels of plasma viral load and host inflammatory cytokines in PBMC were measured by real-time RT-PCR. CD4/CD8 ratio and systemic immune activation markers were examined by flow cytometric analysis of PBMCs. White blood cell and neutrophil counts and C Reactive Protein levels were determined using biochemistry analyzer. The plasma levels of LPS were determined by Tachypleus Amebocyte Lysate (TAL test. RESULTS: The animals inoculated with SIVmac239 became infected as evidenced by the increased plasma levels of SIV RNA and decreased CD4/CD8 ratio. LPS administration of SIV-infected animals induced a transient increase of plasma SIV RNA and immune activation, which was indicated by the elevated expression of the inflammatory cytokines and CD4+HLA-DR+ T cells in PBMCs. CONCLUSIONS: These data support the concept that LPS is a driving factor in systemic immune activation of HIV disease.

  10. Oral immunization of a non-recombinant Lactococcus lactis surface displaying influenza hemagglutinin 1 (HA1 induces mucosal immunity in mice.

    Directory of Open Access Journals (Sweden)

    Pui-Fong Jee

    Full Text Available Mucosal immunization of influenza vaccine is potentially an effective approach for the prevention and control of influenza. The objective of the present study was to evaluate the ability of oral immunization with a non-recombinant Lactococcus lactis displaying HA1/L/AcmA recombinant protein, LL-HA1/L/AcmA, to induce mucosal immune responses and to accord protection against influenza virus infection in mice. The LL-HA1/L/AcmA was orally administered into mice and the immune response was evaluated. Mice immunized with LL-HA1/L/AcmA developed detectable specific sIgA in faecal extract, small intestine wash, BAL fluid and nasal fluid. The results obtained demonstrated that oral immunization of mice with LL-HA1/L/AcmA elicited mucosal immunity in both the gastrointestinal tract and the respiratory tract. The protective efficacy of LL-HA1/L/AcmA in immunized mice against a lethal dose challenge with influenza virus was also assessed. Upon challenge, the non-immunized group of mice showed high susceptibility to influenza virus infection. In contrast, 7/8 of mice orally immunized with LL-HA1/L/AcmA survived. In conclusion, oral administration of LL-HA1/L/AcmA in mice induced mucosal immunity and most importantly, provided protection against lethal influenza virus challenge. These results highlight the potential application of L. lactis as a platform for delivery of influenza virus vaccine.

  11. How Reactive Metabolites Induce an Immune Response That Sometimes Leads to an Idiosyncratic Drug Reaction.

    Science.gov (United States)

    Cho, Tiffany; Uetrecht, Jack

    2017-01-17

    Little is known with certainty about the mechanisms of idiosyncratic drug reactions (IDRs); however, there is substantive evidence that reactive metabolites are involved in most, but not all, IDRs. In addition, evidence also suggests that most IDRs are immune mediated. That raises the question of how reactive metabolites induce an immune response that can lead to an IDR. The dominant hypotheses are the hapten and danger hypotheses. These are complementary hypotheses: a reactive metabolite can act as a hapten to produce neoantigens, and it can also cause cell damage leading to the release of danger-associated molecular pattern molecules that activate antigen presenting cells. Both are required for an immune response. In addition, drugs may induce an immune response through inflammasome activation. We have found examples in which the ability to activate inflammasomes differentiated drugs that cause IDRs from similar drugs that do not. There are other hypotheses that do not involve an immune mechanism such as mitochondrial injury and bile salt export pump (BSEP) inhibition. With some possible exceptions, these hypotheses are unlikely to be able to completely explain IDRs. However, some types of mitochondrial injury or BSEP inhibition could produce danger signals. The major mechanism that protects us from IDRs appears to be immune tolerance. Consistent with this hypothesis, we used checkpoint inhibition to develop the first animal model of idiosyncratic drug-induced liver injury that has the same characteristics as the idiosyncratic injury in humans. This was accomplished by treating Pd-1 -/- mice with anti-CTLA-4 antibodies and amodiaquine. The combination of the Pd-1 -/- mouse and anti-CTLA-4 also unmasks the ability of other drugs such as isoniazid to cause delayed type liver injury. This model should allow rigorous testing of mechanistic hypotheses that was impossible in the past.

  12. Trivalent combination vaccine induces broad heterologous immune responses to norovirus and rotavirus in mice.

    Directory of Open Access Journals (Sweden)

    Kirsi Tamminen

    Full Text Available Rotavirus (RV and norovirus (NoV are the two major causes of viral gastroenteritis (GE in children worldwide. We have developed an injectable vaccine design to prevent infection or GE induced with these enteric viruses. The trivalent combination vaccine consists of NoV capsid (VP1 derived virus-like particles (VLPs of GI-3 and GII-4 representing the two major NoV genogroups and tubular RV recombinant VP6 (rVP6, the most conserved and abundant RV protein. Each component was produced in insect cells by a recombinant baculovirus expression system and combined in vitro. The vaccine components were administered intramuscularly to BALB/c mice either separately or in the trivalent combination. High levels of NoV and RV type specific serum IgGs with high avidity (>50% as well as intestinal IgGs were detected in the immunized mice. Cross-reactive IgG antibodies were also elicited against heterologous NoV VLPs not used for immunization (GII-4 NO, GII-12 and GI-1 VLPs and to different RVs from cell cultures. NoV-specific serum antibodies blocked binding of homologous and heterologous VLPs to the putative receptors, histo-blood group antigens, suggesting broad NoV neutralizing activity of the sera. Mucosal antibodies of mice immunized with the trivalent combination vaccine inhibited RV infection in vitro. In addition, cross-reactive T cell immune responses to NoV and RV-specific antigens were detected. All the responses were sustained for up to six months. No mutual inhibition of the components in the trivalent vaccine combination was observed. In conclusion, the NoV GI and GII VLPs combination induced broader cross-reactive and potentially neutralizing immune responses than either of the VLPs alone. Therefore, trivalent vaccine might induce protective immune responses to the vast majority of circulating NoV and RV genotypes.

  13. TLR 9 involvement in early protection induced by immunization with rPb27 against Paracoccidioidomycosis.

    Science.gov (United States)

    Morais, Elis Araujo; Chame, Daniela Ferreira; Melo, Eliza Mathias; de Carvalho Oliveira, Junnia Alvarenga; de Paula, Ana Cláudia Chagas; Peixoto, Andiara Cardoso; da Silva Santos, Lílian; Gomes, Dawidson Assis; Russo, Remo Castro; de Goes, Alfredo Miranda

    2016-02-01

    Paracoccidioidomycosis is caused by fungi of the Paracoccidioides genus and constitutes the most prevalent deep mycosis in Latin America. Toll-like receptors promote immune response against infectious agents. Recently, it was reported that TLR9 is crucial for mice survival during the first 48 h of P. brasiliensis infection. In this study, we used CPG oligodeoxynucleotide motif as an adjuvant with and without rPb27 to immunize mice against Paracoccidioidomycosis. CPG adjuvant induced differential recruitment of lymphocytes in the inflammatory process and a lower recruitment of neutrophils. In addition, CPG induced the production of pro-inflammatory cytokines such as IL-1β, TNF-α, IL-6 and IL-12; increased phagocytic ability and microbicidal activity by macrophages; and induced differential production of lgG2a and lgG2b, subtypes of Ig. Knockout mice for TLR9 and IL-12 showed higher fungal loads and rates of mortality compared to control mice after 30 days of infection. The association between CPG and rPb27 induced a high level of protection against Paracoccidioidomycosis after the first 30 days of infection but not at 60 days. Our findings demonstrate that TLR 9 plays a role in the protection induced by immunization with rPb27 and confirms the importance of TLR9 in the initial protection against Paracoccidioidomycosis. Copyright © 2015 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

  14. Tyrosine kinase inhibitors induced immune thrombocytopenia in chronic myeloid leukemia?

    Directory of Open Access Journals (Sweden)

    Avital F. Barak

    2011-12-01

    Full Text Available The outcome and quality of life of chronic myeloid leukemia (CML patients has remarkably changed with the treatment of tyrosine kinase inhibitors (TKIs. Currently, hematopoietic stem cell transplantation (HSCT is considered mainly as a third line salvage therapy in cases of TKIs resistance or intolerance. Here we describe a patient with chronic phase CML who developed both resistance and late occurrence of s severe thrombocytopenia on first and second generation TKIs and eventually underwent HSCT. Although the mechanism of the myelosuppression is not fully understood, we showed for the first time the development of dose dependent platelet antibodies in the presence of TKIs, suggesting the possibility of TKIs induced thrombocytopenia. Our case emphasizes that late development of severe myelosuppression during imatinib treatment is probably an important indication for consideration of early HSCT.

  15. PPS nanoparticles as versatile delivery system to induce systemic and broad mucosal immunity after intranasal administration.

    Science.gov (United States)

    Stano, Armando; van der Vlies, André J; Martino, Mikael M; Swartz, Melody A; Hubbell, Jeffrey A; Simeoni, Eleonora

    2011-01-17

    Degradable polymer nanoparticles (NPs, 50 nm) based on polypropylene sulfide (PPS) were conjugated to thiolated antigen and adjuvant proteins by reversible disulfide bonds and evaluated in mucosal vaccination. Ovalbumin was used as a model antigen, and antigen-conjugated NPs were administered intranasally in the mouse. We show penetration of nasal mucosae, transit via M cells, and uptake by antigen-presenting cells in the nasal-associated lymphoid tissue. Ovalbumin-conjugated NPs induced cytotoxic T lymphocytic responses in lung and spleen tissues, as well as humoral response in mucosal airways. Co-conjugation of the TLR5 ligand flagellin further enhanced humoral responses in the airways as well as in the distant vaginal and rectal mucosal compartments and induced cellular immune responses with a Th1 bias, in contrast with free flagellin. The PPS NP platform thus appears interesting as a platform for intranasally-administered mucosal vaccination for inducing broad mucosal immunity. Copyright © 2010 Elsevier Ltd. All rights reserved.

  16. Polysaccharides isolated from Açaí fruit induce innate immune responses.

    Directory of Open Access Journals (Sweden)

    Jeff Holderness

    2011-02-01

    Full Text Available The Açaí (Acai fruit is a popular nutritional supplement that purportedly enhances immune system function. These anecdotal claims are supported by limited studies describing immune responses to the Acai polyphenol fraction. Previously, we characterized γδ T cell responses to both polyphenol and polysaccharide fractions from several plant-derived nutritional supplements. Similar polyphenol and polysaccharide fractions are found in Acai fruit. Thus, we hypothesized that one or both of these fractions could activate γδ T cells. Contrary to previous reports, we did not identify agonist activity in the polyphenol fraction; however, the Acai polysaccharide fraction induced robust γδ T cell stimulatory activity in human, mouse, and bovine PBMC cultures. To characterize the immune response to Acai polysaccharides, we fractionated the crude polysaccharide preparation and tested these fractions for activity in human PBMC cultures. The largest Acai polysaccharides were the most active in vitro as indicated by activation of myeloid and γδ T cells. When delivered in vivo, Acai polysaccharide induced myeloid cell recruitment and IL-12 production. These results define innate immune responses induced by the polysaccharide component of Acai and have implications for the treatment of asthma and infectious disease.

  17. Polysaccharides Isolated from Açaí Fruit Induce Innate Immune Responses

    Science.gov (United States)

    Holderness, Jeff; Schepetkin, Igor A.; Freedman, Brett; Kirpotina, Liliya N.; Quinn, Mark T.; Hedges, Jodi F.; Jutila, Mark A.

    2011-01-01

    The Açaí (Acai) fruit is a popular nutritional supplement that purportedly enhances immune system function. These anecdotal claims are supported by limited studies describing immune responses to the Acai polyphenol fraction. Previously, we characterized γδ T cell responses to both polyphenol and polysaccharide fractions from several plant-derived nutritional supplements. Similar polyphenol and polysaccharide fractions are found in Acai fruit. Thus, we hypothesized that one or both of these fractions could activate γδ T cells. Contrary to previous reports, we did not identify agonist activity in the polyphenol fraction; however, the Acai polysaccharide fraction induced robust γδ T cell stimulatory activity in human, mouse, and bovine PBMC cultures. To characterize the immune response to Acai polysaccharides, we fractionated the crude polysaccharide preparation and tested these fractions for activity in human PBMC cultures. The largest Acai polysaccharides were the most active in vitro as indicated by activation of myeloid and γδ T cells. When delivered in vivo, Acai polysaccharide induced myeloid cell recruitment and IL-12 production. These results define innate immune responses induced by the polysaccharide component of Acai and have implications for the treatment of asthma and infectious disease. PMID:21386979

  18. The anti-tumor efficacy of 3C23K, a glyco-engineered humanized anti-MISRII antibody, in an ovarian cancer model is mainly mediated by engagement of immune effector cells.

    Science.gov (United States)

    Estupina, Pauline; Fontayne, Alexandre; Barret, Jean-Marc; Kersual, Nathalie; Dubreuil, Olivier; Le Blay, Marion; Pichard, Alexandre; Jarlier, Marta; Pugnière, Martine; Chauvin, Maëva; Chardès, Thierry; Pouget, Jean-Pierre; Deshayes, Emmanuel; Rossignol, Alexis; Abache, Toufik; de Romeuf, Christophe; Terrier, Aurélie; Verhaeghe, Lucie; Gaucher, Christine; Prost, Jean-François; Pèlegrin, André; Navarro-Teulon, Isabelle

    2017-06-06

    Ovarian cancer is the leading cause of death in women with gynecological cancers and despite recent advances, new and more efficient therapies are crucially needed. Müllerian Inhibiting Substance type II Receptor (MISRII, also named AMHRII) is expressed in most ovarian cancer subtypes and is a novel potential target for ovarian cancer immunotherapy. We previously developed and tested 12G4, the first murine monoclonal antibody (MAb) against human MISRII. Here, we report the humanization, affinity maturation and glyco-engineering steps of 12G4 to generate the Fc-optimized 3C23K MAb, and the evaluation of its in vivo anti-tumor activity. The epitopes of 3C23K and 12G4 were strictly identical and 3C23K affinity for MISRII was enhanced by a factor of about 14 (KD = 5.5 × 10-11 M vs 7.9 × 10-10 M), while the use of the EMABling® platform allowed the production of a low-fucosylated 3C23K antibody with a 30-fold KD improvement of its affinity to FcγRIIIa. In COV434-MISRII tumor-bearing mice, 3C23K reduced tumor growth more efficiently than 12G4 and its combination with carboplatin was more efficient than each monotherapy with a mean tumor size of 500, 1100 and 100 mm3 at the end of treatment with 3C23K (10 mg/kg, Q3-4D12), carboplatin (60 mg/kg, Q7D4) and 3C23K+carboplatin, respectively. Conversely, 3C23K-FcKO, a 3C23K form without affinity for the FcγRIIIa receptor, did not display any anti-tumor effect in vivo. These results strongly suggested that 3C23K mechanisms of action are mainly Fc-related. In vitro, antibody-dependent cytotoxicity (ADCC) and antibody-dependent cell phagocytosis (ADCP) were induced by 3C23K, as demonstrated with human effector cells. Using human NK cells, 50% of the maximal lysis was obtained with a 46-fold lower concentration of low-fucosylated 3C23K (2.9 ng/ml) than of 3C23K expressed in CHO cells (133.35 ng/ml). As 3C23K induced strong ADCC with human PBMC but almost none with murine PBMC, antibody-dependent cell phagocytosis (ADCP) was

  19. Immunotherapeutic effect of Concholepas hemocyanin in the murine bladder cancer model: evidence for conserved antitumor properties among hemocyanins.

    Science.gov (United States)

    Moltedo, Bruno; Faunes, Fernando; Haussmann, Denise; De Ioannes, Pablo; De Ioannes, Alfredo E; Puente, Javier; Becker, María Inés

    2006-12-01

    We determined the antitumor properties of a newly available hemocyanin obtained from the Chilean gastropod Concholepas concholepas (Biosonda Corp., Santiago, Chile) in a syngeneic heterotopic mouse bladder carcinoma model. Since keyhole limpet hemocyanin (Pierce, Rockford, Illinois) is used increasingly in biomedicine as a carrier for vaccines and an immunotherapeutic agent for bladder transitional cell carcinoma, there is a growing interest in finding new substances that share its potent immunomodulatory properties. Considering that keyhole limpet hemocyanin and Concholepas concholepas hemocyanin differ significantly, it was not possible to predict a priori the antitumor properties of Concholepas concholepas hemocyanin. C3H/He mice were primed with Concholepas concholepas hemocyanin before subcutaneous implantation of mouse bladder tumor-2 cells. Treatment consisted of a subcutaneous dose of Concholepas concholepas hemocyanin (1 mg or 100 mug) at different intervals after implantation. Keyhole limpet hemocyanin and phosphate buffered saline served as positive and negative controls, respectively. In addition, experiments were designed to determine which elements of the immune response were involved in its adjuvant immunostimulatory effect. Mice treated with Concholepas concholepas hemocyanin showed a significant antitumor effect, as demonstrated by decreased tumor growth and incidence, prolonged survival and lack of toxic effects. These effects were similar to those achieved with keyhole limpet hemocyanin. We found that each hemocyanin increased natural killer cell activity but the effect of Concholepas concholepas hemocyanin was stronger. Analysis of serum from treated mice showed an increased interferon-gamma and low interleukin-4, which correlated with antibody isotypes, confirming that hemocyanins induce a T helper type 1 cytokine profile. To our knowledge our results are the first demonstration of the antitumor effect of a hemocyanin other than keyhole limpet

  20. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide.

    OpenAIRE

    Viaud S; Saccheri F; Mignot G; Yamazaki T; Daill\\xere R; Hannani D; Enot DP; Pfirschke C; Engblom C; Pittet MJ; Schlitzer A; Ginhoux F; Apetoh L; Chachaty E; Woerther PL

    2013-01-01

    Cyclophosphamide is one of several clinically important cancer drugs whose therapeutic efficacy is due in part to their ability to stimulate anti-tumor immune responses. Studying mouse models, we demonstrate that cyclophosphamide alters the composition of microbiota in the small intestine and induces the translocation of selected species of Gram+ bacteria into secondary lymphoid organs. There, these bacteria stimulate the generation of a specific subset of “pathogenic” T helper 17 (pTh17) cel...

  1. Spinal cord injury-induced immune deficiency syndrome enhances infection susceptibility dependent on lesion level.

    Science.gov (United States)

    Brommer, Benedikt; Engel, Odilo; Kopp, Marcel A; Watzlawick, Ralf; Müller, Susanne; Prüss, Harald; Chen, Yuying; DeVivo, Michael J; Finkenstaedt, Felix W; Dirnagl, Ulrich; Liebscher, Thomas; Meisel, Andreas; Schwab, Jan M

    2016-03-01

    Pneumonia is the leading cause of death after acute spinal cord injury and is associated with poor neurological outcome. In contrast to the current understanding, attributing enhanced infection susceptibility solely to the patient's environment and motor dysfunction, we investigate whether a secondary functional neurogenic immune deficiency (spinal cord injury-induced immune deficiency syndrome, SCI-IDS) may account for the enhanced infection susceptibility. We applied a clinically relevant model of experimental induced pneumonia to investigate whether the systemic SCI-IDS is functional sufficient to cause pneumonia dependent on spinal cord injury lesion level and investigated whether findings are mirrored in a large prospective cohort study after human spinal cord injury. In a mouse model of inducible pneumonia, high thoracic lesions that interrupt sympathetic innervation to major immune organs, but not low thoracic lesions, significantly increased bacterial load in lungs. The ability to clear the bacterial load from the lung remained preserved in sham animals. Propagated immune susceptibility depended on injury of central pre-ganglionic but not peripheral postganglionic sympathetic innervation to the spleen. Thoracic spinal cord injury level was confirmed as an independent increased risk factor of pneumonia in patients after motor complete spinal cord injury (odds ratio = 1.35, P spinal cord injury directly causes increased risk for bacterial infection in mice as well as in patients. Besides obvious motor and sensory paralysis, spinal cord injury also induces a functional SCI-IDS ('immune paralysis'), sufficient to propagate clinically relevant infection in an injury level dependent manner. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  2. Reduction in diabetes-induced craniofacial defects by maternal immune stimulation.

    Science.gov (United States)

    Hrubec, Terry C; Prater, M Renee; Toops, Kimberly A; Holladay, Steven D

    2006-02-01

    Maternal diabetes can induce a number of developmental abnormalities in laboratory animals and humans, including facial deformities and defects in neural tube closure. The incidence of birth defects in newborns of diabetic women is approximately 3-5 times higher than among non-diabetics. In mice, non-specific activation of the maternal immune system can reduce fetal abnormalities caused by diverse etiologies, including diabetes induced neural tube defects. This study was conducted to determine whether non-specific maternal immune stimulation could reduce diabetes-induced craniofacial defects as well. Maternal immune function was stimulated before streptozocin (STZ) treatment by maternal footpad injection with Freund's complete adjuvant (FCA), maternal intraperitoneal (i.p.) injection with granulocyte-macrophage colony-stimulating factor (GM-CSF), or maternal i.p. injection with interferon-gamma (IFNgamma). Streptozocin (200 mg/kg i.p.) was used to induce hyperglycemia (26-35 mmol blood glucose) in female ICR mice before breeding. Fetuses from 12-18 litters per treatment group, were collected at Day 17 of gestation. Craniofacial defects were observed in fetuses from all hyperglycemic groups. The incidence of defects was significantly decreased in fetuses from dams immune stimulated with IFNgamma or GM-CSF. The most common defects were reduced maxillary and mandibular lengths. Both were prevented by maternal stimulation with GM-CSF. Maternal immune stimulation reduced the incidence of diabetic craniofacial embryopathy. The mechanisms for these protective effects are unknown but may involve maternal or fetal production of cytokines or growth factors that protect the fetus from the dysregulatory effects of hyperglycemia.

  3. CsBAFF, a Teleost B Cell Activating Factor, Promotes Pathogen-Induced Innate Immunity and Vaccine-Induced Adaptive Immunity.

    Directory of Open Access Journals (Sweden)

    Yun Sun

    Full Text Available B cell activating factor (BAFF is a member of the tumor necrosis factor family that is known to play an important role in B cell activation, proliferation, and differentiation in mammals. However, studies of BAFF in teleosts are very limited and its function, in particular that under in vivo conditions, is essentially unknown. In this study, we conducted in vivo as well as in vitro functional analyses of a BAFF homologue (CsBAFF from the teleost fish tongue sole (Cynoglossus semilaevis. CsBAFF is composed of 261 residues and shares moderate sequence identities with known BAFFs of other teleosts. CsBAFF expression was most abundant in immune organs and was upregulated during bacterial infection. Purified recombinant CsBAFF (rCsBAFF bound to tongue sole lymphocytes and promoted cellular proliferation and survival. The results of an in vivo study showed that CsBAFF overexpression in tongue sole significantly enhanced macrophage activation and reduced bacterial infection in fish tissues, whereas knockdown of CsBAFF expression resulted in increased bacterial dissemination and colonization in fish tissues. Furthermore, vaccination studies showed that CsBAFF enhanced the immunoprotection of a DNA vaccine and augmented the production of specific serum antibodies. Taken together, these results provide the first in vivo evidence to indicate that teleost BAFF is an immunostimulator that significantly contributes to the innate antibacterial immune response and vaccine-induced adaptive immune response.

  4. Beryllium-induced immune response in C3H mice

    Energy Technology Data Exchange (ETDEWEB)

    Benson, J.M.; Bice, D.E.; Nikula, K.J. [and others

    1995-12-01

    Studies conducted at ITRI over the past several years have investigated whether Beagle dogs, monkeys, and mice are suitable models for human chronic beryllium-induced lung disease (CBD). Recent studies have focused on the histopathological and immunopathological changes occurring in A/J and C3H/HeJ mice acutely exposed by inhalation to Be metal. Lung lesions in both strains of mice included focal lymphocyte aggregates comprised primarily of B lymphocytes and lesser amounts of T-helper lymphocytes and microgranulomas consisting chiefly of macrophages and T-helper lymphocytes. The distribution of proliferating cells within the microgranulomas was similar to the distribution of T-helper cells. These results strongly suggested that A/J and C3H/HeJ mice responded to inhaled Be metal in a fashion similar to humans in terms of pulmonary lesions and the apparent in situ proliferation of T-helper cells. Results of these studies confirm lymphocyte involvement in the pulmonary response to inhaled Be metal.

  5. Low-dose radiation induces drosophila innate immunity through toll pathway activation

    International Nuclear Information System (INIS)

    Seong, Ki Moon; Kim, Cha Soon; Lee, Byung-Sub; Nam, Seon Young; Yang, Kwang Hee; Kim, Ji-Young; Jin, Young-Woo; Park, Joong-Jean; Min, Kyung-Jin

    2012-01-01

    Numerous studies report that exposing certain organisms to low-dose radiation induces beneficial effects on lifespan, tumorigenesis, and immunity. By analyzing survival after bacterial infection and antimicrobial peptide gene expression in irradiated flies, we demonstrate that low-dose irradiation of Drosophila enhances innate immunity. Low-dose irradiation of flies significantly increased resistance against gram-positive and gram-negative bacterial infections, as well as expression of several antimicrobial peptide genes. Additionally, low-dose irradiation also resulted in a specific increase in expression of key proteins of the Toll signaling pathway and phosphorylated forms of p38 and N-terminal kinase (JNK). These results indicate that innate immunity is activated after low-dose irradiation through Toll signaling pathway in Drosophila. (author)

  6. Molecular Components of the Sporothrix schenckii Complex that Induce Immune Response.

    Science.gov (United States)

    Alba-Fierro, Carlos A; Pérez-Torres, Armando; Toriello, Conchita; Romo-Lozano, Yolanda; López-Romero, Everardo; Ruiz-Baca, Estela

    2016-08-01

    Sporotrichosis is a fungal disease caused by the Sporothrix schenckii complex that includes species such as S. brasiliensis, S. schenckii sensu stricto, S. globosa, S. luriei, S. mexicana, and S. pallida, which exhibit different potentially antigenic molecular components. The immune response of susceptible hosts to control infection and disease caused by these fungi has been little studied. Besides, the fungus-host interaction induces the activation of different types of immune response. This mini-review analyzes and discusses existing reports on the identification and functional characterization of molecules from species of the S. schenckii complex with clinical relevance, and the mechanisms that mediate the type and magnitude of the immune response in experimental models in vivo and in vitro. This knowledge is expected to contribute to the development of protective and therapeutic strategies against sporotrichosis and other mycoses.

  7. Outer membrane vesicles of Gallibacterium anatis induce protective immunity in egg-laying hens

    DEFF Research Database (Denmark)

    Pors, Susanne Elisabeth; Pedersen, Ida Just; Skjerning, Ragnhild Bager

    2016-01-01

    Gallibacterium anatis causes infections in the reproductive tract of egg-laying hens and induce increased mortality and decreased egg production. New prophylactic measures are needed in order to improve animal welfare and production efficiency. Bacterial outer membrane vesicles (OMVs) have...... previously shown promising results in protection against infections and we hypothesized that OMVs could serve as an immunogen to protect egg-laying hens against G. anatis. To investigate the immunogenic potential of G. anatis OMVs, two in vivo studies in egg-laying hens were made. The trials assessedthe...... degree of protection provided by immunization with G. anatis OMV against challenge and the IgY responses in serum after immunization and challenge, respectively. A total of 64 egg-laying hens were included in the trials. OMVs for immunization were produced and purified from a high-producing G. anatis...

  8. Can VHS virus bypass the protective immunity induced by DNA vaccination in rainbow trout?

    DEFF Research Database (Denmark)

    Sepúlveda, Dagoberto; Lorenzen, Niels

    2016-01-01

    pathogenic VHSV isolate in a fish cell line in the presence of neutralizing fish serum (in vitro approach), and in rainbow trout immunized with the VHS DNA vaccine (in vivo approach). For the in vitro approach, the virus collected from the last passage (passaged virus) was as sensitive as the parental virus...... in vaccinated fish was observed in comparison with the parental virus. However, some of the vaccinated fish did get infected and could transmit the infection to naïve cohabitant fish. The results demonstrated that the DNA vaccine induced a robust protection, but also that the immunity was non......DNA vaccines encoding viral glycoproteins have been very successful for induction of protective immunity against diseases caused by rhabdoviruses in cultured fish species. However, the vaccine concept is based on a single viral gene and since RNA viruses are known to possess high variability...

  9. Evidence of a Redox-Dependent Regulation of Immune Responses to Exercise-Induced Inflammation

    Directory of Open Access Journals (Sweden)

    Alexandra Sakelliou

    2016-01-01

    Full Text Available We used thiol-based antioxidant supplementation (n-acetylcysteine, NAC to determine whether immune mobilisation following skeletal muscle microtrauma induced by exercise is redox-sensitive in healthy humans. According to a two-trial, double-blind, crossover, repeated measures design, 10 young men received either placebo or NAC (20 mg/kg/day immediately after a muscle-damaging exercise protocol (300 eccentric contractions and for eight consecutive days. Blood sampling and performance assessments were performed before exercise, after exercise, and daily throughout recovery. NAC reduced the decline of reduced glutathione in erythrocytes and the increase of plasma protein carbonyls, serum TAC and erythrocyte oxidized glutathione, and TBARS and catalase activity during recovery thereby altering postexercise redox status. The rise of muscle damage and inflammatory markers (muscle strength, creatine kinase activity, CRP, proinflammatory cytokines, and adhesion molecules was less pronounced in NAC during the first phase of recovery. The rise of leukocyte and neutrophil count was decreased by NAC after exercise. Results on immune cell subpopulations obtained by flow cytometry indicated that NAC ingestion reduced the exercise-induced rise of total macrophages, HLA+ macrophages, and 11B+ macrophages and abolished the exercise-induced upregulation of B lymphocytes. Natural killer cells declined only in PLA immediately after exercise. These results indicate that thiol-based antioxidant supplementation blunts immune cell mobilisation in response to exercise-induced inflammation suggesting that leukocyte mobilization may be under redox-dependent regulation.

  10. Isolation and Purification of an Antibacterial Protein from Immune Induced Haemolymph of American Cockroach, Periplaneta americana

    Directory of Open Access Journals (Sweden)

    Hamid Reza Basseri

    2016-10-01

    Full Text Available Background: Antimicrobial peptides play a role as effectors substances in the immunity of vertebrate and inverte­brate hosts. In the current study, antimicrobial peptide was isolated from the haemolymph of the American cock­roach, Periplaneta americana.Methods: Micrococcus luteus as Gram-positive bacteria and Escherichia coli as Gram-negative bacteria were candi­date for injection. Induction was done by injecting both bacteria into the abdominal cavity of two groups of cock­roaches separately. The haemolymphs were collected 24 hours after post injection and initially tested against both bacteria. Subsequently, the immune induced haemolymph was purified by high performance liquid chromatography (HPLC to separate the proteins responsible for the antibacterial activity.Results: The non-induced haemolymph did not show any activity against both bacteria whereas induced haemo­lymph exhibited high activity against M. luteus but did less against E. coli. Two fractions showed antibacterial activ­ity against M. luteus. Finally the molecular weight of the isolated antibacterial proteins were determined as 72 kDa and 62 kDa using SDS-PAGE.Conclusion: Induced haemolymph of American cockroaches has the ability to produce peptides to combat against Gram-positive bacteria when an immune challenge is mounted. Further work has to be done to sequence of the pro­tein, which it would be advantageous.

  11. Highly active microbial phosphoantigen induces rapid yet sustained MEK/Erk- and PI-3K/Akt-mediated signal transduction in anti-tumor human gammadelta T-cells.

    Directory of Open Access Journals (Sweden)

    Daniel V Correia

    Full Text Available BACKGROUND: The unique responsiveness of Vgamma9Vdelta2 T-cells, the major gammadelta subset of human peripheral blood, to non-peptidic prenyl pyrophosphate antigens constitutes the basis of current gammadelta T-cell-based cancer immunotherapy strategies. However, the molecular mechanisms responsible for phosphoantigen-mediated activation of human gammadelta T-cells remain unclear. In particular, previous reports have described a very slow kinetics of activation of T-cell receptor (TCR-associated signal transduction pathways by isopentenyl pyrophosphate and bromohydrin pyrophosphate, seemingly incompatible with direct binding of these antigens to the Vgamma9Vdelta2 TCR. Here we have studied the most potent natural phosphoantigen yet identified, (E-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP, produced by Eubacteria and Protozoa, and examined its gammadelta T-cell activation and anti-tumor properties. METHODOLOGY/PRINCIPAL FINDINGS: We have performed a comparative study between HMB-PP and the anti-CD3epsilon monoclonal antibody OKT3, used as a reference inducer of bona fide TCR signaling, and followed multiple cellular and molecular gammadelta T-cell activation events. We show that HMB-PP activates MEK/Erk and PI-3K/Akt pathways as rapidly as OKT3, and induces an almost identical transcriptional profile in Vgamma9(+ T-cells. Moreover, MEK/Erk and PI-3K/Akt activities are indispensable for the cellular effects of HMB-PP, including gammadelta T-cell activation, proliferation and anti-tumor cytotoxicity, which are also abolished upon antibody blockade of the Vgamma9(+ TCR Surprisingly, HMB-PP treatment does not induce down-modulation of surface TCR levels, and thereby sustains gammadelta T-cell activation upon re-stimulation. This ultimately translates in potent human gammadelta T-cell anti-tumor function both in vitro and in vivo upon transplantation of human leukemia cells into lymphopenic mice, CONCLUSIONS/SIGNIFICANCE: The development of

  12. Immune responses against SARS-coronavirus nucleocapsid protein induced by DNA vaccine

    International Nuclear Information System (INIS)

    Zhao Ping; Cao Jie; Zhao Lanjuan; Qin Zhaolin; Ke Jinshan; Pan Wei; Ren Hao; Yu Jianguo; Qi Zhongtian

    2005-01-01

    The nucleocapsid (N) protein of SARS-coronavirus (SARS-CoV) is the key protein for the formation of the helical nucleocapsid during virion assembly. This protein is believed to be more conserved than other proteins of the virus, such as spike and membrane glycoprotein. In this study, the N protein of SARS-CoV was expressed in Escherichia coli DH5α and identified with pooled sera from patients in the convalescence phase of SARS. A plasmid pCI-N, encoding the full-length N gene of SARS-CoV, was constructed. Expression of the N protein was observed in COS1 cells following transfection with pCI-N. The immune responses induced by intramuscular immunization with pCI-N were evaluated in a murine model. Serum anti-N immunoglobulins and splenocytes proliferative responses against N protein were observed in immunized BALB/c mice. The major immunoglobulin G subclass recognizing N protein was immunoglobulin G2a, and stimulated splenocytes secreted high levels of gamma interferon and IL-2 in response to N protein. More importantly, the immunized mice produced strong delayed-type hypersensitivity (DTH) and CD8 + CTL responses to N protein. The study shows that N protein of SARS-CoV not only is an important B cell immunogen, but also can elicit broad-based cellular immune responses. The results indicate that the N protein may be of potential value in vaccine development for specific prophylaxis and treatment against SARS

  13. Tetranychus urticae mites do not mount an induced immune response against bacteria

    Science.gov (United States)

    Santos-Matos, Gonçalo; Wybouw, Nicky; Martins, Nelson E.; Zélé, Flore; Riga, Maria; Leitão, Alexandre B.; Vontas, John; Grbić, Miodrag; Van Leeuwen, Thomas; Magalhães, Sara

    2017-01-01

    The genome of the spider mite Tetranychus urticae, a herbivore, is missing important elements of the canonical Drosophila immune pathways necessary to fight bacterial infections. However, it is not known whether spider mites can mount an immune response and survive bacterial infection. In other chelicerates, bacterial infection elicits a response mediated by immune effectors leading to the survival of infected organisms. In T. urticae, infection by either Escherichia coli or Bacillus megaterium did not elicit a response as assessed through genome-wide transcriptomic analysis. In line with this, spider mites died within days even upon injection with low doses of bacteria that are non-pathogenic to Drosophila. Moreover, bacterial populations grew exponentially inside the infected spider mites. By contrast, Sancassania berlesei, a litter-dwelling mite, controlled bacterial proliferation and resisted infections with both Gram-negative and Gram-positive bacteria lethal to T. urticae. This differential mortality between mite species was absent when mites were infected with heat-killed bacteria. Also, we found that spider mites harbour in their gut 1000-fold less bacteria than S. berlesei. We show that T. urticae has lost the capacity to mount an induced immune response against bacteria, in contrast to other mites and chelicerates but similarly to the phloem feeding aphid Acyrthosiphon pisum. Hence, our results reinforce the putative evolutionary link between ecological conditions regarding exposure to bacteria and the architecture of the immune response. PMID:28592670

  14. Tumor necrosis factor-α-induced protein 1 and immunity to hepatitis B virus

    Science.gov (United States)

    Lin, Marie C; Lee, Nikki P; Zheng, Ning; Yang, Pai-Hao; Wong, Oscar G; Kung, Hsiang-Fu; Hui, Chee-Kin; Luk, John M; Lau, George Ka-Kit

    2005-01-01

    AIM: To compare the gene expression profile in a pair of HBV-infected twins. METHODS: The gene expression profile was compared in a pair of HBV-infected twins. RESULTS: The twins displayed different disease outcomes. One acquired natural immunity against HBV, whereas the other became a chronic HBV carrier. Eighty-eight and forty-six genes were found to be up- or down-regulated in their PBMCs, respectively. Tumor necrosis factor-alpha-induced protein 1 (TNF-αIP1) that expressed at a higher level in the HBV-immune twins was identified and four pairs of siblings with HBV immunity by RT-PCR. However, upon HBV core antigen stimulation, TNF-αIP1 was downregulated in PBMCs from subjects with immunity, whereas it was slightly upregulated in HBV carriers. Bioinformatics analysis revealed a K+ channel tetramerization domain in TNF-αIP1 that shares a significant homology with some human, mouse, and C elegan proteins. CONCLUSION: TNF-αIP1 may play a role in the innate immunity against HBV. PMID:16437679

  15. Response of Selenium and Selenogenome in Immune Tissues to LPS-Induced Inflammatory Reactions in Pigs.

    Science.gov (United States)

    Sun, Lv-Hui; Pi, Ding-An; Zhao, Ling; Wang, Xiu-Ying; Zhu, Luo-Yi; Qi, De-Sheng; Liu, Yu-Lan

    2017-05-01

    Circulating concentration of the essential trace element selenium (Se) was significantly lower in inflammatory disorders. Although Se plays physiological roles mainly through the function of 25 selenoproteins, the response of the selenogenome in immune tissues during inflammatory reactions remains unclear. The objective of this study was to determine the Se retention and selenogenome expression in immune tissues during the lipopolysaccharide (LPS)-induced inflammatory response in porcine. A total of 12 male pigs were randomly divided into two groups and injected with LPS or saline. After 4 h postinjection, blood samples were collected and pigs were euthanized. Pigs challenged with LPS had 36.8 and 16.6 % lower (P response of Txnrd2, Txnrd3, Sep15, Selh, Seli, Seln, Selo, Selt, Selx, and Sephs2 to inflammatory reaction in immune tissues were newly illustrated in this study. In conclusion, the LPS-induced inflammatory response impaired Se metabolism and was associated with dysregulation of the selenogenome expression in immune tissues.

  16. Safety and immune regulatory properties of canine induced pluripotent stem cell-derived mesenchymal stem cells.

    Science.gov (United States)

    Chow, Lyndah; Johnson, Valerie; Regan, Dan; Wheat, William; Webb, Saiphone; Koch, Peter; Dow, Steven

    2017-12-01

    Mesenchymal stem cells (MSCs) exhibit broad immune modulatory activity in vivo and can suppress T cell proliferation and dendritic cell activation in vitro. Currently, most MSC for clinical usage are derived from younger donors, due to ease of procurement and to the superior immune modulatory activity. However, the use of MSC from multiple unrelated donors makes it difficult to standardize study results and compare outcomes between different clinical trials. One solution is the use of MSC derived from induced pluripotent stem cells (iPSC); as iPSC-derived MSC have nearly unlimited proliferative potential and exhibit in vitro phenotypic stability. Given the value of dogs as a spontaneous disease model for pre-clinical evaluation of stem cell therapeutics, we investigated the functional properties of canine iPSC-derived MSC (iMSC), including immune modulatory properties and potential for teratoma formation. We found that canine iMSC downregulated expression of pluripotency genes and appeared morphologically similar to conventional MSC. Importantly, iMSC retained a stable phenotype after multiple passages, did not form teratomas in immune deficient mice, and did not induce tumor formation in dogs following systemic injection. We concluded therefore that iMSC were phenotypically stable, immunologically potent, safe with respect to tumor formation, and represented an important new source of cells for therapeutic modulation of inflammatory disorders. Copyright © 2017. Published by Elsevier B.V.

  17. Club cells surviving influenza A virus infection induce temporary nonspecific antiviral immunity.

    Science.gov (United States)

    Hamilton, Jennifer R; Sachs, David; Lim, Jean K; Langlois, Ryan A; Palese, Peter; Heaton, Nicholas S

    2016-04-05

    A brief window of antigen-nonspecific protection has been observed after influenza A virus (IAV) infection. Although this temporary immunity has been assumed to be the result of residual nonspecific inflammation, this period of induced immunity has not been fully studied. Because IAV has long been characterized as a cytopathic virus (based on its ability to rapidly lyse most cell types in culture), it has been a forgone conclusion that directly infected cells could not be contributing to this effect. Using a Cre recombinase-expressing IAV, we have previously shown that club cells can survive direct viral infection. We show here not only that these cells can eliminate all traces of the virus and survive but also that they acquire a heightened antiviral response phenotype after surviving. Moreover, we experimentally demonstrate temporary nonspecific viral immunity after IAV infection and show that surviving cells are required for this phenotype. This work characterizes a virally induced modulation of the innate immune response that may represent a new mechanism to prevent viral diseases.

  18. Safety and immune regulatory properties of canine induced pluripotent stem cell-derived mesenchymal stem cells

    Directory of Open Access Journals (Sweden)

    Lyndah Chow

    2017-12-01

    Full Text Available Mesenchymal stem cells (MSCs exhibit broad immune modulatory activity in vivo and can suppress T cell proliferation and dendritic cell activation in vitro. Currently, most MSC for clinical usage are derived from younger donors, due to ease of procurement and to the superior immune modulatory activity. However, the use of MSC from multiple unrelated donors makes it difficult to standardize study results and compare outcomes between different clinical trials. One solution is the use of MSC derived from induced pluripotent stem cells (iPSC; as iPSC-derived MSC have nearly unlimited proliferative potential and exhibit in vitro phenotypic stability. Given the value of dogs as a spontaneous disease model for pre-clinical evaluation of stem cell therapeutics, we investigated the functional properties of canine iPSC-derived MSC (iMSC, including immune modulatory properties and potential for teratoma formation. We found that canine iMSC downregulated expression of pluripotency genes and appeared morphologically similar to conventional MSC. Importantly, iMSC retained a stable phenotype after multiple passages, did not form teratomas in immune deficient mice, and did not induce tumor formation in dogs following systemic injection. We concluded therefore that iMSC were phenotypically stable, immunologically potent, safe with respect to tumor formation, and represented an important new source of cells for therapeutic modulation of inflammatory disorders.

  19. Radiation-induced antitumor properties of vitamin B5 (pantothenic acid) and its effect on mitomycin C activity: experiments in vitro.

    Science.gov (United States)

    Schittl, Heike; Getoff, Nikola

    2007-01-01

    Vitamin B5 (pantothenic acid) shows a strongly pronounced antitumor effect under the influence of ionizing radiation. In the frame of experiments in vitro (model: Escherichia coli bacteria, AB1157) performed under the exact knowledge of concentration and kind of the free radicals acting in the various aqueous media (pH 7.4) the following was established: (i) vitamin B5 possesses a very intense antitumor property, (ii) it exerts a strong synergistic effect on mitomycin C (MMC), (iii) the oxidizing species (OH*, O2*-) appears to be most important in the initiation of the observed effect. The generated radiolytic products from vitamin B5 very likely also play an important role in this respect.

  20. Infection-specific phosphorylation of glutamyl-prolyl tRNA synthetase induces antiviral immunity

    Science.gov (United States)

    Lee, Eun-Young; Lee, Hyun-Cheol; Kim, Hyun-Kwan; Jang, Song Yee; Park, Seong-Jun; Kim, Yong-Hoon; Kim, Jong Hwan; Hwang, Jungwon; Kim, Jae-Hoon; Kim, Tae-Hwan; Arif, Abul; Kim, Seon-Young; Choi, Young-Ki; Lee, Cheolju; Lee, Chul-Ho; Jung, Jae U; Fox, Paul L; Kim, Sunghoon; Lee, Jong-Soo; Kim, Myung Hee

    2016-01-01

    The mammalian cytoplasmic multi-tRNA synthetase complex (MSC) is a depot system that regulates non-translational cellular functions. Here we found that the MSC component glutamyl-prolyl-tRNA synthetase (EPRS) switched its function following viral infection and exhibited potent antiviral activity. Infection-specific phosphorylation of EPRS at Ser990 induced its dissociation from the MSC, after which it was guided to the antiviral signaling pathway, where it interacted with PCBP2, a negative regulator of mitochondrial antiviral signaling protein (MAVS) that is critical for antiviral immunity. This interaction blocked PCBP2-mediated ubiquitination of MAVS and ultimately suppressed viral replication. EPRS-haploid (Eprs+/−) mice showed enhanced viremia and inflammation and delayed viral clearance. This stimulus-inducible activation of MAVS by EPRS suggests an unexpected role for the MSC as a regulator of immune responses to viral infection. PMID:27595231

  1. BAFF and APRIL from Activin A-Treated Dendritic Cells Upregulate the Antitumor Efficacy of Dendritic Cells In Vivo.

    Science.gov (United States)

    Shurin, Michael R; Ma, Yang; Keskinov, Anton A; Zhao, Ruijing; Lokshin, Anna; Agassandian, Marianna; Shurin, Galina V

    2016-09-01

    The members of the TGFβ superfamily play a key role in regulating developmental and homeostasis programs by controlling differentiation, proliferation, polarization, and survival of different cell types. Although the role of TGFβ1 in inflammation and immunity is well evident, the contribution of other TGFβ family cytokines in the modulation of the antitumor immune response remains less documented. Here we show that activin A triggers SMAD2 and ERK1/2 pathways in dendritic cells (DC) expressing type I and II activin receptors, and upregulates production of the TNFα family cytokines BAFF (TALL-1, TNFSF13B) and APRIL (TALL-2, TNFSF13A), which is blocked by SMAD2 and ERK1/2 inhibitors, respectively. BAFF and APRIL derived from activin A-treated DCs upregulate proliferation and survival of T cells expressing the corresponding receptors, BAFF-R and TACI. In vivo, activin A-stimulated DCs demonstrate a significantly increased ability to induce tumor-specific CTLs and inhibit the growth of melanoma and lung carcinoma, which relies on DC-derived BAFF and APRIL, as knockdown of the BAFF and APRIL gene expression in activin A-treated DCs blocks augmentation of their antitumor potential. Although systemic administration of activin A, BAFF, or APRIL for the therapeutic purposes is not likely due to the pluripotent effects on malignant and nonmalignant cells, our data open a novel opportunity for improving the efficacy of DC vaccines. In fact, a significant augmentation of the antitumor activity of DC pretreated with activin A and the proven role of DC-derived BAFF and APRIL in the induction of antitumor immunity in vivo support this direction. Cancer Res; 76(17); 4959-69. ©2016 AACR. ©2016 American Association for Cancer Research.

  2. Exposure to low infective doses of HCV induces cellular immune responses without consistently detectable viremia or seroconversion in chimpanzees

    International Nuclear Information System (INIS)

    Shata, Mohamed Tarek; Tricoche, Nancy; Perkus, Marion; Tom, Darley; Brotman, Betsy; McCormack, Patricia; Pfahler, Wolfram; Lee, Dong-Hun; Tobler, Leslie H.; Busch, Michael; Prince, Alfred M.

    2003-01-01

    In hepatitis C virus (HCV) infection, there is accumulating data suggesting the presence of cellular immune responses to HCV in exposed but seemingly uninfected populations. Some studies have suggested cross-reactive antigens rather than prior HCV exposure as the main reason for the immune responses. In this study we address this question by analyzing the immune response of chimpanzees that have been sequentially exposed to increasing doses of HCV virions. The level of viremia, as well as the immune responses to HCV at different times after virus inoculation, were examined. Our data indicate that HCV infective doses as low as 1-10 RNA (+) virions induce detectable cellular immune responses in chimpanzees without consistently detectable viremia or persistent seroconversion. However, increasing the infective doses of HCV to 100 RNA (+) virions overcame the low-inoculum-induced immune response and produced high-level viremia followed by seroconversion

  3. Probiotic Cheese Attenuates Exercise-induced Immune Suppression In Wistar Rats

    OpenAIRE

    Lollo P.C.B.; Cruz A.G.; Morato P.N.; Moura C.S.; Carvalho-Silva L.B.; Oliveira C.A.F.; Faria J.A.F.; Amaya-Farfan J.

    2012-01-01

    Intense physical activity results in a substantial volume of stress and hence a significant probability of immunosuppression in athletes, with milk proteins being, perhaps, the most recommended protein supplements. Consumption of a probiotic cheese can attenuate immune suppression induced by exhausting exercise in rats. A popular Brazilian fresh cheese (Minas Frescal cheese) containing Lactobacillus acidophilus LA14 and Bifidobacterium longum BL05 was fed for 2 wk to adult Wistar rats, which ...

  4. Study on the Immunomodulation Effect of Isodon japonicus Extract via Splenocyte Function and NK Anti-Tumor Activity

    Directory of Open Access Journals (Sweden)

    Kyung-A Hwang

    2012-04-01

    Full Text Available Here we investigated the potential immune-enhancing activity of Isodon japonicus on murine splenocyte and natural-killer (NK cells in vitro. The ethanol extract of I. japonicus significantly enhanced the proliferation of splenocyte and induced the significant enhancement of NK cells’ activity against tumor cells (YAC-1. In addition, I. japonicus increased the production of interferon (IFN-γ and tumor necrosis factor (TNF-α, suggesting that the increase in NK cell cytotoxicity could be due to the enhancement of the NK cell production of both cytokines. Taken together, I. japonicus extract inhibited the growth of human leukemia cells (K562 by 74%. Our observation indicated that the anti-tumor effects of I. japonicus may be attributed to its ability to serve as a stimulant of NK anti-tumor activity. In addition, our results support the development of functional food studies on I. japonicus.

  5. Maize Prolamins Could Induce a Gluten-Like Cellular Immune Response in Some Celiac Disease Patients

    Science.gov (United States)

    Ortiz-Sánchez, Juan P.; Cabrera-Chávez, Francisco; Calderón de la Barca, Ana M.

    2013-01-01

    Celiac disease (CD) is an autoimmune-mediated enteropathy triggered by dietary gluten in genetically prone individuals. The current treatment for CD is a strict lifelong gluten-free diet. However, in some CD patients following a strict gluten-free diet, the symptoms do not remit. These cases may be refractory CD or due to gluten contamination; however, the lack of response could be related to other dietary ingredients, such as maize, which is one of the most common alternatives to wheat used in the gluten-free diet. In some CD patients, as a rare event, peptides from maize prolamins could induce a celiac-like immune response by similar or alternative pathogenic mechanisms to those used by wheat gluten peptides. This is supported by several shared features between wheat and maize prolamins and by some experimental results. Given that gluten peptides induce an immune response of the intestinal mucosa both in vivo and in vitro, peptides from maize prolamins could also be tested to determine whether they also induce a cellular immune response. Hypothetically, maize prolamins could be harmful for a very limited subgroup of CD patients, especially those that are non-responsive, and if it is confirmed, they should follow, in addition to a gluten-free, a maize-free diet. PMID:24152750

  6. Hepatitis B virus infection and vaccine-induced immunity in Madrid (Spain).

    Science.gov (United States)

    Pedraza-Flechas, Ana María; García-Comas, Luis; Ordobás-Gavín, María; Sanz-Moreno, Juan Carlos; Ramos-Blázquez, Belén; Astray-Mochales, Jenaro; Moreno-Guillén, Santiago

    2014-01-01

    To estimate the prevalence of hepatitis B virus (HBV) infection and vaccine-induced immunity in the region of Madrid, and to analyze their evolution over time. An observational, analytical, cross-sectional study was carried out in the population aged 16-80 years between 2008 and 2009. This was the last of four seroprevalence surveys in the region of Madrid. The prevalence of HBV infection and vaccine-induced immunity was estimated using multivariate logistic models and were compared with the prevalences in the 1989, 1993 and 1999 surveys. In the population aged 16-80 years, the prevalence of HBV infection was 11.0% (95% CI: 9.8-12.3) and that of chronic infection was 0.7% (95% CI: 0.5-1.1). The prevalence of vaccine-induced immunity in the population aged 16-20 years was 73.0% (95% CI: 70.0-76.0). Compared with previous surveys, there was a decrease in the prevalence of HBV infection. Based on the prevalence of chronic infection (<1%), Madrid is a region with low HBV endemicity. Preventive strategies against HBV should especially target the immigrant population. Copyright © 2013. Published by Elsevier Espana.

  7. Immune response induced by candidate Sarcoptes scabiei var. cuniculi DNA vaccine encoding paramyosin in mice.

    Science.gov (United States)

    Gu, Xiaobin; Xie, Yue; Wang, Shuxian; Peng, Xuerong; Lai, Songjia; Yang, Guangyou

    2014-07-01

    Sarcoptes scabiei is the causal agent of the highly contagious disease sarcoptic mange (scabies) that affects animals and humans worldwide. An increasing number of cases of treatment failure is being reported because of drug resistance. The development of a specific vaccine would be a sustainable option for control of this disease. In this study, we cloned and expressed a S. scabiei gene encoding paramyosin (PAR) and investigated the immune response elicited by DNA encoding PAR in mice. The ability of the DNA vaccine to express antigen in COS-7 cells was confirmed by RT-PCR and IFA. The immune response induced by DNA vaccine was investigated by ELISA, splenocyte proliferation assay, and cytokine production assay. Compared to the pVAX1 control group, the PAR DNA vaccination group showed the higher levels of IgG, IgG1, IgG2a, IgE, IgM, stronger lymphocyte proliferation in mouse spleen, and larger production of IL-2, IL-4, IL-5, and IFN-γ in the supernatant of cultures from splenocytes. These results indicated that the PAR DNA vaccine induced a mixed Th1/Th2 response in mice. In conclusion, our results revealed that the S. scabiei PAR DNA vaccine induced both a humoral and cellular immune response, which would provide basic data for the further study to develop an effective vaccine against sarcoptic mange.

  8. Biotechnological approaches for field applications of chitooligosaccharides (COS) to induce innate immunity in plants.

    Science.gov (United States)

    Das, Subha Narayan; Madhuprakash, Jogi; Sarma, P V S R N; Purushotham, Pallinti; Suma, Katta; Manjeet, Kaur; Rambabu, Samudrala; Gueddari, Nour Eddine El; Moerschbacher, Bruno M; Podile, Appa Rao

    2015-03-01

    Plants have evolved mechanisms to recognize a wide range of pathogen-derived molecules and to express induced resistance against pathogen attack. Exploitation of induced resistance, by application of novel bioactive elicitors, is an attractive alternative for crop protection. Chitooligosaccharide (COS) elicitors, released during plant fungal interactions, induce plant defenses upon recognition. Detailed analyses of structure/function relationships of bioactive chitosans as well as recent progress towards understanding the mechanism of COS sensing in plants through the identification and characterization of their cognate receptors have generated fresh impetus for approaches that would induce innate immunity in plants. These progresses combined with the application of chitin/chitosan/COS in disease management are reviewed here. In considering the field application of COS, however, efficient and large-scale production of desired COS is a challenging task. The available methods, including chemical or enzymatic hydrolysis and chemical or biotechnological synthesis to produce COS, are also reviewed.

  9. Immunization of Mice with a Live Transconjugant Shigella Hybrid Strain Induced Th1 and Th17 Cell-Mediated Immune Responses and Confirmed Passive Protection Against Heterologous Shigellae.

    Science.gov (United States)

    Nag, D; Koley, H; Sinha, R; Mukherjee, P; Sarkar, C; Withey, J H; Gachhui, R

    2016-02-01

    An avirulent, live transconjugant Shigella hybrid (LTSHΔstx) strain was constructed in our earlier study by introducing a plasmid vector, pPR1347, into a Shiga toxin gene deleted Shigella dysenteriae 1. Three successive oral administrations of LTSHΔstx to female adult mice produced comprehensive passive heterologous protection in their offspring against challenge with wild-type shigellae. Production of NO and different cytokines such asIL-12p70, IL-1β and IL-23 in peritoneal mice macrophages indicated that LTSHΔstx induced innate and adaptive immunity in mice. Furthermore, production of IFN-γ, IL-10 and IL-17 in LTSH-primed splenic CD4+ T cell suggested that LTSHΔstx may induce Th1 and Th17 cell-mediated immune responses. Exponential increase of the serum IgG and IgA titre against whole shigellae was observed in immunized adult mice during and after the immunization with the highest peak on day 35. Antigen-specific sIgA was also determined from intestinal lavage of immunized mice. The stomach extracts of neonates from immunized mice, mainly containing mother's milk, contained significant levels of anti-LTSHΔstx immunoglobulin. These studies suggest that the LTSHΔstx could be a new live oral vaccine candidate against shigellosis in the near future. © 2015 The Foundation for the Scandinavian Journal of Immunology.

  10. Killer B Lymphocytes and their Fas Ligand Positive Exosomes as Inducers of Immune Tolerance

    Directory of Open Access Journals (Sweden)

    Steven Karl Lundy

    2015-03-01

    Full Text Available Induction of immune tolerance is a key process by which the immune system is educated to modulate reactions against benign stimuli such as self-antigens and commensal microbes. Understanding and harnessing the natural mechanisms of immune tolerance may become an increasingly useful strategy for treating many types of allergic and autoimmune diseases, as well as for improving the acceptance of solid organ transplants. Our laboratory and others have been interested in the natural ability of some B lymphocytes to express the death-inducing molecule Fas ligand (FasL, and their ability to kill T helper (TH lymphocytes. We have recently shown that experimental transformation of human B cells by a non-replicative variant of Epstein-Barr virus (EBV consistently resulted in high expression of functional FasL protein. The production and release of FasL+ exosomes that co-expressed MHC Class II molecules and had the capacity to kill antigen-specific TH cells was also observed. Several lines of evidence indicate that FasL+ B cells and FasL+MHCII+ exosomes have important roles in natural immune tolerance and have a great deal of therapeutic potential. Taken together, these findings suggest that EBV-immortalized human B lymphoblastoid cell lines could be used as cellular factories for FasL+ exosomes, which would be employed to therapeutically establish and/or regain immune tolerance toward specific antigens. The goals of this review are to summarize current knowledge of the roles of FasL+ B cells and exosomes in immune regulation, and to suggest methods of manipulating killer B cells and FasL+ exosomes for clinical purposes.

  11. Room Temperature Stable PspA-Based Nanovaccine Induces Protective Immunity

    Directory of Open Access Journals (Sweden)

    Danielle A. Wagner-Muñiz

    2018-03-01

    Full Text Available Streptococcus pneumoniae is a major causative agent of pneumonia, a debilitating disease particularly in young and elderly populations, and is the leading worldwide cause of death in children under the age of five. While there are existing vaccines against S. pneumoniae, none are protective across all serotypes. Pneumococcal surface protein A (PspA, a key virulence factor of S. pneumoniae, is an antigen that may be incorporated into future vaccines to address the immunological challenges presented by the diversity of capsular antigens. PspA has been shown to be immunogenic and capable of initiating a humoral immune response that is reactive across approximately 94% of pneumococcal strains. Biodegradable polyanhydrides have been studied as a nanoparticle-based vaccine (i.e., nanovaccine platform to stabilize labile proteins, to provide adjuvanticity, and enhance patient compliance by providing protective immunity in a single dose. In this study, we designed a room temperature stable PspA-based polyanhydride nanovaccine that eliminated the need for a free protein component (i.e., 100% encapsulated within the nanoparticles. Mice were immunized once with the lead nanovaccine and upon challenge, presented significantly higher survival rates than animals immunized with soluble protein alone, even with a 25-fold reduction in protein dose. This lead nanovaccine formulation performed similarly to protein adjuvanted with Alum, however, with much less tissue reactogenicity at the site of immunization. By eliminating the free PspA from the nanovaccine formulation, the lead nanovaccine was efficacious after being stored dry for 60 days at room temperature, breaking the need for maintaining the cold chain. Altogether, this study demonstrated that a single dose PspA-based nanovaccine against S. pneumoniae induced protective immunity and provided thermal stability when stored at room temperature for at least 60 days.

  12. DNA vaccine constructs expressing Mycobacterium tuberculosis-specific genes induce immune responses.

    Science.gov (United States)

    Hanif, S N M; Al-Attiyah, R; Mustafa, A S

    2010-11-01

    RD1 PE35, PPE68, EsxA, EsxB and RD9 EsxV genes are present in Mycobacterium tuberculosis genome but deleted in Mycobacterium bovis BCG. The aim of this study was to clone these genes into DNA vaccine vectors capable of expressing them in eukaryotic cells as fusion proteins, fused with immunostimulatory signal peptides of human interleukin-2 (hIL-2) and tissue plasminogen activator (tPA), and evaluate the recombinant DNA vaccine constructs for induction of antigen-specific cellular immune responses in mice. DNA corresponding to the aforementioned RD1 and RD9 genes was cloned into DNA vaccine plasmid vectors pUMVC6 and pUMVC7 (with hIL-2 and tPA signal peptides, respectively), and a total of 10 recombinant DNA vaccine constructs were obtained. BALB/c mice were immunized with the parent and recombinant plasmids and their spleen cells were tested for antigen-induced proliferation with antigens of M. tuberculosis and pure proteins corresponding to the cloned genes. The results showed that antigen-specific proliferation responses were observed for a given antigen only with spleen cells of mice immunized with the homologous recombinant DNA vaccine construct. The mice immunized with the parent plasmids did not show positive immune responses to any of the antigens of the cloned genes. The ability of the DNA vaccine constructs to elicit cellular immune responses makes them an attractive weapon as a safer vaccine candidate for preventive and therapeutic applications against tuberculosis. © 2010 The Authors. Scandinavian Journal of Immunology © 2010 Blackwell Publishing Ltd.

  13. The Effect of Radiation on the Immune Response to Cancers

    Directory of Open Access Journals (Sweden)

    Bonggoo Park

    2014-01-01

    Full Text Available In cancer patients undergoing radiation therapy, the beneficial effects of radiation can extend beyond direct cytotoxicity to tumor cells. Delivery of localized radiation to tumors often leads to systemic responses at distant sites, a phenomenon known as the abscopal effect which has been attributed to the induction and enhancement of the endogenous anti-tumor innate and adaptive immune response. The mechanisms surrounding the abscopal effect are diverse and include trafficking of lymphocytes into the tumor microenvironment, enhanced tumor recognition and killing via up-regulation of tumor antigens and antigen presenting machinery and, induction of positive immunomodulatory pathways. Here, we discuss potential mechanisms of radiation-induced enhancement of the anti-tumor response through its effect on the host immune system and explore potential combinational immune-based strategies such as adoptive cellular therapy using ex vivo expanded NK and T cells as a means of delivering a potent effector population in the context of radiation-enhanced anti-tumor immune environment.

  14. Co-expression of Interleukin-15 Enhances the Protective Immune Responses Induced by Immunization with a Murine Malaria MVA-Based Vaccine Encoding the Circumsporozoite Protein.

    Science.gov (United States)

    Parra, Marcela; Liu, Xia; Derrick, Steven C; Yang, Amy; Molina-Cruz, Alvaro; Barillas-Mury, Carolina; Zheng, Hong; Thao Pham, Phuong; Sedegah, Martha; Belmonte, Arnel; Litilit, Dianne D; Waldmann, Thomas A; Kumar, Sanjai; Morris, Sheldon L; Perera, Liyanage P

    2015-01-01

    Malaria remains a major global public health problem with an estimated 200 million cases detected in 2012. Although the most advanced candidate malaria vaccine (RTS,S) has shown promise in clinical trials, its modest efficacy and durability have created uncertainty about the impact of RTS,S immunization (when used alone) on global malaria transmission. Here we describe the development and characterization of a novel modified vaccinia virus Ankara (MVA)-based malaria vaccine which co-expresses the Plasmodium yoelii circumsporozoite protein (CSP) and IL-15. Vaccination/challenge studies showed that C57BL/6 mice immunized with the MVA-CSP/IL15 vaccine were protected significantly better against a P. yoelii 17XNL sporozoite challenge than either mice immunized with an MVA vaccine expressing only CSP or naïve controls. Importantly, the levels of total anti-CSP IgG were elevated about 100-fold for the MVA-CSP/IL15 immunized group compared to mice immunized with the MVA-CSP construct that does not express IL-15. Among the IgG subtypes, the IL-15 expressing MVA-CSP vaccine induced levels of IgG1 (8 fold) and IgG2b (80 fold) higher than the MVA-CSP construct. The significantly enhanced humoral responses and protection detected after immunization with the MVA-CSP/IL15 vaccine suggest that this IL-15 expressing MVA construct could be considered in the development of future malaria immunization strategies.

  15. Retnla (relmalpha/fizz1 suppresses helminth-induced Th2-type immunity.

    Directory of Open Access Journals (Sweden)

    John T Pesce

    2009-04-01

    Full Text Available Retnla (Resistin-like molecule alpha/FIZZ1 is induced during Th2 cytokine immune responses. However, the role of Retnla in Th2-type immunity is unknown. Here, using Retnla(-/- mice and three distinct helminth models, we show that Retnla functions as a negative regulator of Th2 responses. Pulmonary granuloma formation induced by the eggs of the helminth parasite Schistosoma mansoni is dependent on IL-4 and IL-13 and associated with marked increases in Retnla expression. We found that both primary and secondary pulmonary granuloma formation were exacerbated in the absence of Retlna. The number of granuloma-associated eosinophils and serum IgE titers were also enhanced. Moreover, when chronically infected with S. mansoni cercariae, Retnla(-/- mice displayed significant increases in granulomatous inflammation in the liver and the development of fibrosis and progression to hepatosplenic disease was markedly augmented. Finally, Retnla(-/- mice infected with the gastrointestinal (GI parasite Nippostrongylus brasiliensis had intensified lung pathology to migrating larvae, reduced fecundity, and accelerated expulsion of adult worms from the intestine, suggesting Th2 immunity was enhanced. When their immune responses were compared, helminth infected Retnla(-/- mice developed stronger Th2 responses, which could be reversed by exogenous rRelmalpha treatment. Studies with several cytokine knockout mice showed that expression of Retnla was dependent on IL-4 and IL-13 and inhibited by IFN-gamma, while tissue localization and cell isolation experiments indicated that eosinophils and epithelial cells were the primary producers of Retnla in the liver and lung, respectively. Thus, the Th2-inducible gene Retnla suppresses resistance to GI nematode infection, pulmonary granulomatous inflammation, and fibrosis by negatively regulating Th2-dependent responses.

  16. Estradiol-induced vaginal mucus inhibits antigen penetration and CD8(+) T cell priming in response to intravaginal immunization.

    Science.gov (United States)

    Seavey, Matthew M; Mosmann, Tim R

    2009-04-14

    Although vaginal immunization has been explored as a strategy to induce mucosal immunity in the female reproductive tract, this site displays unique immunological features that probably evolved to inhibit anti-paternal T cell responses after insemination to allow successful pregnancy. We previously demonstrated that estradiol, which induces an estrus-like state, prevented CD8(+) T cell priming during intravaginal immunization of mice. We now show that estradiol prevented antigen loading of vaginal antigen presenting cells (APCs) after intravaginal immunization. Histological examination confirmed that estradiol prevented penetration of peptide antigen into the vaginal wall. Removal of the estradiol-induced mucus barrier by mucinase partially restored antigen loading of vaginal APC and CD8(+) T cell proliferation in vivo. The estradiol-induced mucus barrier may thus prevent exposure to antigens delivered intravaginally, supplementing additional estradiol-dependent mechanism(s) that inhibit CD8(+) T cell priming after insemination or vaginal vaccination.

  17. Estradiol-induced vaginal mucus inhibits antigen penetration and CD8+ T cell priming in response to intravaginal immunization

    Science.gov (United States)

    Seavey, Matthew M.; Mosmann, Tim R.

    2010-01-01

    Although vaginal immunization has been explored as a strategy to induce mucosal immunity in the female reproductive tract, this site displays unique immunological features that probably evolved to inhibit anti-paternal T cell responses after insemination to allow successful pregnancy. We previously demonstrated that estradiol, which induces an estrus-like state, prevented CD8+ T cell priming during intravaginal immunization of mice. We now show that estradiol prevented antigen loading of vaginal antigen presenting cells (APC) after intravaginal immunization. Histological examination confirmed that estradiol prevented penetration of peptide antigen into the vaginal wall. Removal of the estradiol-induced mucus barrier by mucinase partially restored antigen loading of vaginal APC and CD8+ T cell proliferation in vivo. The estradiol-induced mucus barrier may thus prevent exposure to antigens delivered intravaginally, supplementing additional estradiol-dependent mechanism(s) that inhibit CD8+ T cell priming after insemination or vaginal vaccination. PMID:19428849

  18. IL4-induced gene 1 promotes tumor growth by shaping the immune microenvironment in melanoma.

    Science.gov (United States)

    Bod, Lloyd; Lengagne, Renée; Wrobel, Ludovic; Ramspott, Jan Philipp; Kato, Masashi; Avril, Marie-Françoise; Castellano, Flavia; Molinier-Frenkel, Valérie; Prévost-Blondel, Armelle

    2017-01-01

    Amino acid catabolizing enzymes emerged as a crucial mechanism used by tumors to dampen immune responses. The L-phenylalanine oxidase IL-4 induced gene 1 (IL4I1) is expressed by tumor-associated myeloid cells of most solid tumors, including melanoma. We previously provided the only evidence that IL4I1 accelerates tumor growth by limiting the CD8 + T cell mediated immune response, in a mouse model of melanoma cell transplantation. Here, we explored the role of IL4I1 in Ret mice, a spontaneous model of melanoma. We found that IL4I1 was expressed by CD11b + myeloid cells and that its activity correlated with disease aggressiveness. IL4I1 did not enhance tumor cell proliferation or angiogenesis, but orchestrated the remodeling of the immune compartment within the primary tumor. Indeed, the inactivation of IL4I1 limited the recruitment of polymorphonuclear myeloid-derived suppressor cells and enhanced the infiltration by Th1 and cytotoxic T cells, thus delaying tumor development and metastatic dissemination. Accordingly, human primary melanomas that were poorly infiltrated by IL4I1 + cells exhibited a higher density of CD8 + T cells. Collectively, our findings strengthen the rationale for therapeutic targeting of IL4I1 as one of the key immune regulators.

  19. Interleukin-17-induced protein lipocalin 2 is dispensable for immunity to oral candidiasis.

    Science.gov (United States)

    Ferreira, Maria Carolina; Whibley, Natasha; Mamo, Anna J; Siebenlist, Ulrich; Chan, Yvonne R; Gaffen, Sarah L

    2014-03-01

    Oropharyngeal candidiasis (OPC; thrush) is an opportunistic fungal infection caused by the commensal microbe Candida albicans. Immunity to OPC is strongly dependent on CD4+ T cells, particularly those of the Th17 subset. Interleukin-17 (IL-17) deficiency in mice or humans leads to chronic mucocutaneous candidiasis, but the specific downstream mechanisms of IL-17-mediated host defense remain unclear. Lipocalin 2 (Lcn2; 24p3; neutrophil gelatinase-associated lipocalin [NGAL]) is an antimicrobial host defense factor produced in response to inflammatory cytokines, particularly IL-17. Lcn2 plays a key role in preventing iron acquisition by bacteria that use catecholate-type siderophores, and lipocalin 2(-/-) mice are highly susceptible to infection by Escherichia coli and Klebsiella pneumoniae. The role of Lcn2 in mediating immunity to fungi is poorly defined. Accordingly, in this study, we evaluated the role of Lcn2 in immunity to oral infection with C. albicans. Lcn2 is strongly upregulated following oral infection with C. albicans, and its expression is almost entirely abrogated in mice with defective IL-17 signaling (IL-17RA(-/-) or Act1(-/-) mice). However, Lcn2(-/-) mice were completely resistant to OPC, comparably to wild-type (WT) mice. Moreover, Lcn2 deficiency mediated protection from OPC induced by steroid immunosuppression. Therefore, despite its potent regulation during C. albicans infection, Lcn2 is not required for immunity to mucosal candidiasis.

  20. C3d enhanced DNA vaccination induced humoral immune response to glycoprotein C of pseudorabies virus

    International Nuclear Information System (INIS)

    Tong Tiezhu; Fan Huiying; Tan Yadi; Xiao Shaobo; Ling Jieyu; Chen Huanchun; Guo Aizhen

    2006-01-01

    Murine C3d were utilized to enhance immunogenicity of pseudorabies virus (PrV) gC DNA vaccination. Three copies of C3d and four copies of CR2-binding domain M28 4 were fused, respectively, to truncated gC gene encoding soluble glycoprotein C (sgC) in pcDNA3.1. BALB/c mice were, respectively, immunized with recombinant plasmids, blank vector, and inactivated vaccine. The antibody ELISA titer for sgC-C3d 3 DNA was 49-fold more than that for sgC DNA, and the neutralizing antibody obtained 8-fold rise. Protection of mice from death after lethal PrV (316 LD 5 ) challenge was augmented from 25% to 100%. Furthermore, C3d fusion increased Th2-biased immune response by inducing IL-4 production. The IL-4 level for sgC-C3d 3 DNA immunization approached that for the inactivated vaccine. Compared to C3d, M28 enhanced sgC DNA immunogenicity to a lesser extent. In conclusion, we demonstrated that murine C3d fusion significantly enhanced gC DNA immunity by directing Th1-biased to a balanced and more effective Th1/Th2 response

  1. Role of Bacterial Exopolysaccharides as Agents in Counteracting Immune Disorders Induced by Herpes Virus

    Directory of Open Access Journals (Sweden)

    Concetta Gugliandolo

    2015-08-01

    Full Text Available Extreme marine environments, such as the submarine shallow vents of the Eolian Islands (Italy, offer an almost unexplored source of microorganisms producing unexploited and promising biomolecules for pharmaceutical applications. Thermophilic and thermotolerant bacilli isolated from Eolian vents are able to produce exopolysaccharides (EPSs with antiviral and immunomodulatory effects against Herpes simplex virus type 2 (HSV-2. HSV-2 is responsible for the most common and continuously increasing viral infections in humans. Due to the appearance of resistance to the available treatments, new biomolecules exhibiting different mechanisms of action could provide novel agents for treating viral infections. The EPSs hinder the HSV-2 replication in human peripheral blood mononuclear cells (PBMC but not in WISH (Wistar Institute Susan Hayflic cells line, indicating that cell-mediated immunity was involved in the antiviral activity. High levels of Th1-type cytokines were detected in PBMC treated with all EPSs, while Th2-type cytokines were not induced. These EPSs are water soluble exopolymers able to stimulate the immune response and thus contribute to the antiviral immune defense, acting as immunomodulators. As stimulants of Th1 cell-mediated immunity, they could lead to the development of novel drugs as alternative in the treatment of herpes virus infections, as well as in immunocompromised host.

  2. Sunlight Effects on Immune System: Is There Something Else in addition to UV-Induced Immunosuppression?

    Directory of Open Access Journals (Sweden)

    D. H. González Maglio

    2016-01-01

    Full Text Available Sunlight, composed of different types of radiation, including ultraviolet wavelengths, is an essential source of light and warmth for life on earth but has strong negative effects on human health, such as promoting the malignant transformation of skin cells and suppressing the ability of the human immune system to efficiently detect and attack malignant cells. UV-induced immunosuppression has been extensively studied since it was first described by Dr. Kripke and Dr. Fisher in the late 1970s. However, skin exposure to sunlight has not only this and other unfavorable effects, for example, mutagenesis and carcinogenesis, but also a positive one: the induction of Vitamin D synthesis, which performs several roles within the immune system in addition to favoring bone homeostasis. The impact of low levels of UV exposure on the immune system has not been fully reported yet, but it bears interesting differences with the suppressive effect of high levels of UV radiation, as shown by some recent studies. The aim of this article is to put some ideas in perspective and pose some questions within the field of photoimmunology based on established and new information, which may lead to new experimental approaches and, eventually, to a better understanding of the effects of sunlight on the human immune system.