Journal Articles

Oncolytic viruses

Therapies based on tumor-targeting cytolytic viruses, including oncolytic viruses armed with immunomodulatory transgenes

Intratumoral immunotherapy with XCL1 and sFlt3L encoded in recombinant Semliki Forest Virus-derived vectors fosters dendritic cell-mediated T cell cross-priming

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Multiple lines of evidence indicate a critical role for antigen cross-presentation by conventional BATF3-dependent type 1 classical dendritic cells (cDC1) in CD8-mediated antitumor immunity. Flt3L and XCL1 respectively constitute a key growth/differentiation factor and a potent and specific chemoattractant for cDC1. To exploit their antitumor functions in local immunotherapy, we prepared Semliki Forest Virus (SFV)-based vectors encoding XCL1 and soluble Flt3L (sFlt3L). These vectors readily conferred transgene expression to tumor cells in culture and when engrafted as subcutaneous mouse tumor models. In syngeneic mice, intratumoral injection of SFV-XCL1-sFlt3L (SFV-XF) delayed progression of MC38- and B16-derived tumors. Therapeutic activity was observed and exerted additive effects in combination with anti-PD-1, anti-CD137, or CTLA-4 immunostimulatory monoclonal antibodies. Therapeutic effects were abolished by CD8beta T cell depletion and were enhanced by CD4 T cell depletion, but not by Treg pre-depletion with anti-CD25 mAb. Antitumor effects were also abolished in BATF3- and IFNAR-deficient mice. In B16-OVA tumors, SFV-XF increased the number of infiltrating CD8 T cells, including those recognizing OVA. Consistently, following intratumoral SFV-XF treatment courses, we observed increased BATF3-dependent cDC1 among B16-OVA tumor-infiltrating leukocytes. Such an intratumoral increase was not seen in MC38-derived tumors, but both resident and migratory cDC1 were boosted in SFV-XF-treated MC38 tumor-draining lymph nodes. In conclusion, viral gene transfer of sFlt3L and XCL1 is feasible, safe, and biologically active in mice, exerting antitumor effects that can be potentiated by CD4 T cell depletion.

Author Info: (1) Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA). (2) Oncology

Author Info: (1) Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA). (2) Oncology, Center for Applied Medical Research (CIMA). University of Navarra. (3) Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA). (4) University Clinic, University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA). (5) Immunology, CIMA+ (Canada). (6) Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA). (7) Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA). (8) Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA). (9) CIMA Research Foundation. (10) Gene therapy, CIMA+ (Canada). (11) Division of Hepatology and Gene Therapy, University of Navarra, Center for Applied Medical Research (CIMA). (12) Research Department of Haematology, University College London Cancer Institute. (13) Program of Immunology and Immunotherapy, Center for Applied Medical Research, University of Navarra. (14) Immunobiology lab, Centro Nacional de Investigaciones Cardiovasculares (CNIC). (15) Division of Gene Therapy and Regulation of Gene Expression, Center for Applied Medical Research (CIMA), and Instituto de Investigacion Sanitaria de Navarra (IdISNA). (16) Immunology, CIMA and CUN imelero@unav.es.

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LONG-TERM SURVIVAL IN PATIENTS RESPONDING TO ANTI-PD-1/PD-L1 THERAPY AND DISEASE OUTCOME UPON TREATMENT DISCONTINUATION

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PURPOSE: Anti-PD-(L)1 can provide overall survival (OS) benefits over conventional treatments for patients with many different cancer types. However, the long-term outcome of cancer patients responding to these therapies remains unknown. This study is an exploratory study that aimed to describe the long-term survival of patients responding to anti-PD-(L)1 monotherapy across multiple cancer types. EXPERIMENTAL DESIGN: Data from patients treated with an anti-PD-(L)1 monotherapy in a phase 1 trial at Gustave Roussy were retrospectively analyzed over a period of 5 years. All cancer types (n=19) were included. Clinical and biological factors associated with response, long-term survival, and secondary refractory disease were studied. RESULTS: Among 262 eligible patients, the overall objective response rate was 29%. The median progression-free survival of responder patients (RPs) at 3 months was 30 months, and the median OS of RP was not reached after a median follow-up of 34 months. In RPs, 3- and 5-year OS percentages were 84% and 64%, respectively.No death occurred in the 21 complete responders (CRs) during the overall follow-up. However, many partial responders (PRs) showed subsequent tumor relapses to treatment. Long responders (response (3)2 years) represented 11.8% of the overall population.These finding should be validated in further prospective studies. CONCLUSIONS: There are currently no differences in therapeuticstrategies between CRs and PRs to anti-PD-(L)1. We found a striking difference in OS between these two types of responses. Our results are in favor of evaluating patient stratifications strategies and intensification of treatments when tumor lesions of a partial responder to immunotherapy stop improving.

Author Info: (1) Institut Gustave Roussy. (2) U1018, Gustave Roussy, INSERM, Univ. Paris-Sud, Universite Paris Saclay. (3) Departement d'Innovation Therapeutique et des Essais Precoces (DITEP), Gustave Roussy

Author Info: (1) Institut Gustave Roussy. (2) U1018, Gustave Roussy, INSERM, Univ. Paris-Sud, Universite Paris Saclay. (3) Departement d'Innovation Therapeutique et des Essais Precoces (DITEP), Gustave Roussy. (4) Radiology, Gustave Roussy Cancer Centre. (5) Departement de l'imagerie medicale, Service d'imagerie diagnostique, Gustave Roussy. (6) Gustave Roussy. (7) Gustave Roussy. (8) Val de Marne, Gustave Roussy Cancer Center. (9) Drug Development Department (DITEP), Gustave Roussy Cancer Campus and University Paris-Sud. (10) Gustave Roussy. (11) Department of Drug Development, Gustave Roussy. (12) DITEP (Departement d'Innovations Therapeutiques et Essais Precoces), Inserm Unit U981, Universite Paris Saclay, Universite Paris-Sud, Gustave Roussy. (13) Drug Development Department (DITEP), Gustave Roussy. (14) DITEP, Institut Gustave Roussy. (15) Drug development department (DITEP), Institute Gustave Roussy. (16) Head of the Oncology Innovative Medicines, Medimmune. (17) INSERM U981, Gustave Roussy. (18) Medical Oncology, Gustave Roussy. (19) Institut Gustave Roussy AURELIEN.MARABELLE@gustaveroussy.fr.

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Differential regulation of PD-L1 expression by immune and tumor cells in NSCLC and the response to treatment with atezolizumab (anti-PD-L1)

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Programmed death-ligand 1 (PD-L1) expression on tumor cells (TCs) by immunohistochemistry is rapidly gaining importance as a diagnostic for the selection or stratification of patients with non-small cell lung cancer (NSCLC) most likely to respond to single-agent checkpoint inhibitors. However, at least two distinct patterns of PD-L1 expression have been observed with potential biological and clinical relevance in NSCLC: expression on TC or on tumor-infiltrating immune cells (ICs). We investigated the molecular and cellular characteristics associated with PD-L1 expression in these distinct cell compartments in 4,549 cases of NSCLC. PD-L1 expression on IC was more prevalent and likely reflected IFN-gamma-induced adaptive regulation accompanied by increased tumor-infiltrating lymphocytes and effector T cells. High PD-L1 expression on TC, however, reflected an epigenetic dysregulation of the PD-L1 gene and was associated with a distinct histology described by poor immune infiltration, sclerotic/desmoplastic stroma, and mesenchymal molecular features. Importantly, durable clinical responses to atezolizumab (anti-PD-L1) were observed in patients with tumors expressing high PD-L1 levels on either TC alone [40% objective response rate (ORR)] or IC alone (22% ORR). Thus, PD-L1 expression on TC or IC can independently attenuate anticancer immunity and emphasizes the functional importance of IC in regulating the antitumor T cell response.

Author Info: (1) Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA 94080; kowanetz.marcin@gene.com mellman.ira@gene.com. (2) Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA 94080. (3)

Author Info: (1) Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA 94080; kowanetz.marcin@gene.com mellman.ira@gene.com. (2) Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA 94080. (3) Medical Oncology, Yale Cancer Center, New Haven, CT 06510. (4) Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA 94080. (5) HistoGeneX, 2610 Antwerp, Belgium. (6) Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, United Kingdom. (7) Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA 94080. (8) Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX 77054. (9) Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065. (10) Hematology and Oncology, Columbia University, New York, NY 10027. (11) Sarah Cannon Research Institute, Nashville, TN 37203. (12) Oncology Program, Virginia Cancer Specialists, Fairfax, VA 22031. (13) Medical Oncology, University of Colorado Cancer Center, Denver, CO 80045. (14) Oncology, Jewish General Hospital, Montreal, QC, Canada H3T 1E2. (15) Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA 94080. (16) Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA 94080. (17) Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA 94080. (18) Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA 94080. (19) Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA 94080. (20) Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA 94080. (21) Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA 94080. (22) Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA 94080. (23) Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA 94080. (24) Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA 94080. (25) Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA 94080. (26) Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA 94080. (27) Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA 94080. (28) Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA 94080; kowanetz.marcin@gene.com mellman.ira@gene.com. (29) Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA 94080. (30) Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA 94080.

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Suppression of STING associated with LKB1 loss in KRAS-driven lung cancer

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KRAS-driven lung cancers frequently inactivate TP53 and/or STK11/LKB1, defining tumor subclasses with emerging clinical relevance. Specifically, KRAS-LKB1 (KL) mutant lung cancers are particularly aggressive, lack PD-L1, and respond poorly to immune checkpoint blockade (ICB). The mechanistic basis for this impaired immunogenicity, despite the overall high mutational load of KRAS mutant lung cancers, remains obscure. Here we report that LKB1 loss results in marked silencing of STING expression and insensitivity to cytoplasmic double strand DNA (dsDNA) sensing. This effect is mediated at least in part by hyperactivation of DNMT1 and EZH2 activity related to elevated S-adenylmethionine (SAM) levels, and reinforced by DNMT1 upregulation. Ectopic expression of STING in KL cells engages IRF3 and STAT1 signaling downstream of TBK1 and impairs cellular fitness, due to the pathologic accumulation of cytoplasmic mitochondrial dsDNA associated with mitochondrial dysfunction. Thus, silencing of STING avoids these negative consequences of LKB1 inactivation, while facilitating immune escape.

Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute DBARBIE@PARTNERS.ORG. (2) Department of Medical Oncology, Dana-Farber Cancer Institute. (3) Belfer Center for Applied Cancer Science, Dana-Farber

Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute DBARBIE@PARTNERS.ORG. (2) Department of Medical Oncology, Dana-Farber Cancer Institute. (3) Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute. (4) Virginia Tech. (5) Department of Medical Oncology, Dana-Farber Cancer Institute. (6) Department of Medical Oncology, Dana-Farber Cancer Institute. (7) Department of Medical Oncology, Dana-Farber Cancer Institute. (8) Department of Human Genetics, Graduate School Biomedical Sciences, Tokushima University, Tokushima, Japan. (9) Department of Respiratory Medicine, Juntendo University. (10) Department of Medical Oncology, Dana-Farber Cancer Institute. (11) Department of Pediatric Oncology, Dana-Farber Cancer Institute. (12) Department of Medical Oncology, Dana-Farber Cancer Institute. (13) Department of Pathology, Brigham and Women's Hospital. (14) Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute. (15) Department of Medical Oncology, Dana-Farber Cancer Institute. (16) Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai. (17) MCB Department, Brown University.

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Differential and Overlapping Immune Programs Regulated by IRF3 and IRF5 in Plasmacytoid Dendritic Cells

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We examined the signaling pathways and cell type-specific responses of IFN regulatory factor (IRF) 5, an immune-regulatory transcription factor. We show that the protein kinases IKKalpha, IKKbeta, IKKepsilon, and TANK-binding kinase 1 each confer IRF5 phosphorylation/dimerization, thus extending the family of IRF5 activator kinases. Among primary human immune cell subsets, we found that IRF5 is most abundant in plasmacytoid dendritic cells (pDCs). Flow cytometric cell imaging revealed that IRF5 is specifically activated by endosomal TLR signaling. Comparative analyses revealed that IRF3 is activated in pDCs uniquely through RIG-I-like receptor (RLR) signaling. Transcriptomic analyses of pDCs show that the partitioning of TLR7/IRF5 and RLR/IRF3 pathways confers differential gene expression and immune cytokine production in pDCs, linking IRF5 with immune regulatory and proinflammatory gene expression. Thus, TLR7/IRF5 and RLR-IRF3 partitioning serves to polarize pDC response outcome. Strategies to differentially engage IRF signaling pathways should be considered in the design of immunotherapeutic approaches to modulate or polarize the immune response for specific outcome.

Author Info: (1) Department of Immunology, Center for Innate Immunity and Immune Disease, University of Washington, Seattle, WA 98109. Department of Biomedical Sciences, City University of Hong

Author Info: (1) Department of Immunology, Center for Innate Immunity and Immune Disease, University of Washington, Seattle, WA 98109. Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong Special Administrative Region; and. (2) Department of Immunology, Center for Innate Immunity and Immune Disease, University of Washington, Seattle, WA 98109. (3) Laboratory of Hematology and Oncology, Graduate School of Health Sciences, Niigata University, Niigata, Niigata Prefecture 950-2181, Japan. (4) Department of Immunology, Center for Innate Immunity and Immune Disease, University of Washington, Seattle, WA 98109. (5) Department of Immunology, Center for Innate Immunity and Immune Disease, University of Washington, Seattle, WA 98109. (6) Department of Immunology, Center for Innate Immunity and Immune Disease, University of Washington, Seattle, WA 98109; mgale@uw.edu looy@uw.edu. (7) Department of Immunology, Center for Innate Immunity and Immune Disease, University of Washington, Seattle, WA 98109; mgale@uw.edu looy@uw.edu.

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In situ administration of cytokine combinations induces tumor regression in mice

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BACKGROUND: Recent advances in cancer immunotherapy suggest a possibility of harnessing the immune system to defeat malignant tumors, but the complex immunosuppressive microenvironment confines the therapeutic benefits to a minority of patients with solid tumors. METHODS: A lentivector-based inducible system was established to evaluate the therapeutic effect of cytokines in established tumors. Intratumoral injection of certain cytokine combination in syngeneic tumor models was conducted to assess the therapeutic potentials. FINDINGS: Doxycycline (Dox)-induced local expression of cytokine combinations exhibites a strong synergistic effect, leading to complete regression of tumors. Notably, IL12+GMCSF+IL2 expression induces eradication of tumors in all mice tolerated with this treatment, including those bearing large tumors of ~15mm in diameter, and generates intensive systemic antitumor immunity. Other combinations with similar immune regulatory roles also induce tumor elimination in most of mice. Moreover, intratumoral injection of chitosan/IL12+GMCSF+IL2 solution induces a complete response in all the tested syngeneic tumor models, regardless of various tumor immunograms. INTERPRETATION: Administration of certain cytokine combinations in tumor microenvironment induces a strong synergistic antitumor response, including the recruitment of large amount of immune cells and the generation of systemic antitumor immunity. It provides a versatile method for the immunotherapy of intractable malignant neoplasms. FUND: There is no external funding supporting this study.

Author Info: (1) Mianyi Biotech Corporation, Chongqing 401332, China. Electronic address: zhangjinyu@tsinghua.org.cn. (2) Center for Life Sciences, Tsinghua University, Beijing 100084, China. (3) Beijing Chaoyang District Animal

Author Info: (1) Mianyi Biotech Corporation, Chongqing 401332, China. Electronic address: zhangjinyu@tsinghua.org.cn. (2) Center for Life Sciences, Tsinghua University, Beijing 100084, China. (3) Beijing Chaoyang District Animal Disease Control Center, Beijing 100018, China.

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Positive & Negative Roles of Innate Effector Cells in Controlling Cancer Progression

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Innate immune cells are active at the front line of host defense against pathogens and now appear to play a range of roles under non-infectious conditions as well, most notably in cancer. Establishing the balance of innate immune responses is critical for the "flavor" of these responses and subsequent adaptive immunity and can be either "good or bad" in controlling cancer progression. The importance of innate NK cells in tumor immune responses has already been extensively studied over the last few decades, but more recently several relatively mono- or oligo-clonal [i.e., (semi-) invariant] innate T cell subsets received substantial interest in tumor immunology including invariant natural killer T (iNKT), gammadelta-T and mucosal associated invariant T (MAIT) cells. These subsets produce high levels of various pro- and/or anti-inflammatory cytokines/chemokines reflecting their capacity to suppress or stimulate immune responses. Survival of patients with cancer has been linked to the frequencies and activation status of NK, iNKT, and gammadelta-T cells. It has become clear that NK, iNKT, gammadelta-T as well as MAIT cells all have physiological roles in anti-tumor responses, which emphasize their possible relevance for tumor immunotherapy. A variety of clinical trials has focused on manipulating NK, iNKT, and gammadelta-T cell functions as a cancer immunotherapeutic approach demonstrating their safety and potential for achieving beneficial therapeutic effects, while the exploration of MAIT cell related therapies is still in its infancy. Current issues limiting the full therapeutic potential of these innate cell subsets appear to be related to defects and suppressive properties of these subsets that, with the right stimulus, might be reversed. In general, how innate lymphocytes are activated appears to control their subsequent abilities and consequent impact on adaptive immunity. Controlling these potent regulators and mediators of the immune system should enable their protective roles to dominate and their deleterious potential (in the specific context of cancer) to be mitigated.

Author Info: (1) Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, Netherlands. (2) Department of Medical Oncology, VU University Medical Center, Amsterdam, Netherlands

Author Info: (1) Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, Netherlands. (2) Department of Medical Oncology, VU University Medical Center, Amsterdam, Netherlands. (3) Department of Medical Oncology, VU University Medical Center, Amsterdam, Netherlands. (4) Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, Netherlands. (5) Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom. Harvard Medical School, Brigham and Women's Hospital, Boston, MA, United States. Agenus, Inc., Lexington, MA, United States.

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MK2 Regulates Macrophage Chemokine Activity and Recruitment to Promote Colon Tumor Growth

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A major risk factor for colon cancer growth and progression is chronic inflammation. We have shown that the MAPK-activated protein kinase 2 (MK2) pathway is critical for colon tumor growth in colitis-associated and spontaneous colon cancer models. This pathway is known to regulate expression of the tumor-promoting cytokines, IL-1, IL-6, and TNF-alpha. However, little is known about the ability of MK2 to regulate chemokine production. This is the first study to demonstrate this pathway also regulates the chemokines, MCP-1, Mip-1alpha, and Mip-2alpha (MMM). We show that these chemokines induce tumor cell growth and invasion in vitro and that MK2 inhibition suppresses tumor cell production of chemokines and reverses the resulting pro-tumorigenic effects. Addition of MMM to colon tumors in vivo significantly enhances tumor growth in control tumors and restores tumor growth in the presence of MK2 inhibition. We also demonstrate that MK2 signaling is critical for chemokine expression and macrophage influx to the colon tumor microenvironment. MK2 signaling in macrophages was essential for inflammatory cytokine/chemokine production, whereas MK2(-/-) macrophages or MK2 inhibition suppressed cytokine expression. We show that addition of bone marrow-derived macrophages to the tumor microenvironment enhances tumor growth in control tumors and restores tumor growth in tumors treated with MK2 inhibitors, while addition of MK2(-/-) macrophages had no effect. This is the first study to demonstrate the critical role of the MK2 pathway in chemokine production, macrophage influx, macrophage function, and tumor growth.

Author Info: (1) Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States. (2) Department of Molecular Genetics and Microbiology

Author Info: (1) Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States. (2) Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States. (3) Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States. (4) Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States. (5) Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Texas Medical Branch, Galveston, TX, United States. (6) Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Texas Medical Branch, Galveston, TX, United States. (7) Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States.

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Elimination of CD4(low)HLA-G(+) T cells overcomes castration-resistance in prostate cancer therapy

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Androgen deprivation therapy (ADT) is a main treatment for prostate cancer (PCa) but the disease often recurs and becomes castration-resistant in nearly all patients. Recent data implicate the involvement of immune cells in the development of this castration-resistant prostate cancer (CRPC). In particular, T cells have been found to be expanded in both PCa patients and mouse models shortly after androgen deprivation. However, whether or which of the T cell subtypes play an important role during the development of CRPC is unknown. Here we identified a novel population of CD4(low)HLA-G(+) T cells that undergo significant expansion in PCa patients after ADT. In mouse PCa models, a similar CD4(low) T cell population expands during the early stages of CRPC onset. These cells are identified as IL-4-expressing TH17 cells, and are shown to be associated with CRPC onset in patients and essential for the development of CRPC in mouse models. Mechanistically, CD4(low)HLA-G(+) T cells drive androgen-independent growth of prostate cancer cells by modulating the activity and migration of CD11b(low)F4/80(hi) macrophages. Furthermore, following androgen deprivation, elevated PGE2-EP2 signaling inhibited the expression of CD4 in thymocytes, and subsequently induced the polarization of CD4(low) naive T cells towards the IL-4-expressing TH17 phenotype via up-regulation of IL23R. Therapeutically, inactivating PGE2 signaling with celecoxib at a time when CD4(low)HLA-G(+) T cells appeared, but not immediately following androgen deprivation, dramatically suppressed the onset of CRPC. Collectively, our results indicate that an unusual population of CD4(low)HLA-G(+) T cells is essential for the development of CRPC and point to a new therapeutic avenue of combining ADT with PGE2 inhibition for the treatment of prostate cancer.

Author Info: (1) State Key Laboratory of Oncogenes and Related Genes, Renji-MedX stem Cell Research Center, Ren Ji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University

Author Info: (1) State Key Laboratory of Oncogenes and Related Genes, Renji-MedX stem Cell Research Center, Ren Ji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200030, China. Med-X Research Institute & School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200030, China. (2) Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China. (3) State Key Laboratory of Oncogenes and Related Genes, Renji-MedX stem Cell Research Center, Ren Ji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200030, China. Med-X Research Institute & School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200030, China. (4) State Key Laboratory of Oncogenes and Related Genes, Renji-MedX stem Cell Research Center, Ren Ji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200030, China. (5) State Key Laboratory of Oncogenes and Related Genes, Renji-MedX stem Cell Research Center, Ren Ji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200030, China. Med-X Research Institute & School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200030, China. (6) State Key Laboratory of Oncogenes and Related Genes, Renji-MedX stem Cell Research Center, Ren Ji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200030, China. Med-X Research Institute & School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200030, China. (7) State Key Laboratory of Oncogenes and Related Genes, Renji-MedX stem Cell Research Center, Ren Ji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200030, China. (8) Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China. (9) State Key Laboratory of Oncogenes and Related Genes, Renji-MedX stem Cell Research Center, Ren Ji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200030, China. yanzh@sjtu.edu.cn. Med-X Research Institute & School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200030, China. yanzh@sjtu.edu.cn. (10) State Key Laboratory of Oncogenes and Related Genes, Renji-MedX stem Cell Research Center, Ren Ji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200030, China. gao.weiqiang@sjtu.edu.cn. Med-X Research Institute & School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200030, China. gao.weiqiang@sjtu.edu.cn.

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Human Dendritic Cells: Ontogeny and Their Subsets in Health and Disease

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Dendritic cells (DCs) are a type of cells derived from bone marrow that represent 1% or less of the total hematopoietic cells of any lymphoid organ or of the total cell count of the blood or epithelia. Dendritic cells comprise a heterogeneous population of cells localized in different tissues where they act as sentinels continuously capturing antigens to present them to T cells. Dendritic cells are uniquely capable of attracting and activating naive CD4(+) and CD8(+) T cells to initiate and modulate primary immune responses. They have the ability to coordinate tolerance or immunity depending on their activation status, which is why they are also considered as the orchestrating cells of the immune response. The purpose of this review is to provide a general overview of the current knowledge on ontogeny and subsets of human dendritic cells as well as their function and different biological roles.

Author Info: (1) Departamento de Microbiologia y Parasitologia, Facultad de Medicina, Universidad Nacional Autonoma de Mexico, Ciudad de Mexico 04510, Mexico. solano-sandra@hotmail.com. (2) Departamento de Microbiologia, Centro

Author Info: (1) Departamento de Microbiologia y Parasitologia, Facultad de Medicina, Universidad Nacional Autonoma de Mexico, Ciudad de Mexico 04510, Mexico. solano-sandra@hotmail.com. (2) Departamento de Microbiologia, Centro de Investigacion en Ciencias de la Salud, Facultad de Ciencias de la Salud (CICSA), Universidad Anahuac Mexico Campus Norte, Estado de Mexico 52786, Mexico. soniatovart@gmail.com. (3) Departamento de Microbiologia, Centro de Investigacion en Ciencias de la Salud, Facultad de Ciencias de la Salud (CICSA), Universidad Anahuac Mexico Campus Norte, Estado de Mexico 52786, Mexico. sofia.tron@hotmail.com. (4) Departamento de Microbiologia, Centro de Investigacion en Ciencias de la Salud, Facultad de Ciencias de la Salud (CICSA), Universidad Anahuac Mexico Campus Norte, Estado de Mexico 52786, Mexico. aweisers@gmail.com. (5) Departamento de Microbiologia, Centro de Investigacion en Ciencias de la Salud, Facultad de Ciencias de la Salud (CICSA), Universidad Anahuac Mexico Campus Norte, Estado de Mexico 52786, Mexico. diego.alvarez.hernandez@hotmail.com. (6) Medical IMPACT, Infectious Diseases Department, Mexico City 53900, Mexico. giorgio.franyuti@gmail.com. (7) Medical IMPACT, Infectious Diseases Department, Mexico City 53900, Mexico. tapkov@hotmail.com. (8) Coordinacion del Centro de Investigacion en Ciencias de la Salud, Facultad de Ciencias de la Salud (CICSA), Universidad Anahuac Mexico Campus Norte, Estado de Mexico 52786, Mexico. jose.ibarra@anahuac.mx. (9) Unidad de Investigacion UNAM-INC, Division Investigacion, Facultad de Medicina, Universidad Nacional Autonoma de Mexico-Instituto Nacional de Cardiologia "Ignacio Chavez", Mexico City 14080, Mexico. lgutierr@unam.mx. (10) Departamento de Microbiologia, Centro de Investigacion en Ciencias de la Salud, Facultad de Ciencias de la Salud (CICSA), Universidad Anahuac Mexico Campus Norte, Estado de Mexico 52786, Mexico. vazquezrosalino@yahoo.com.

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