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      PTPN2 regulates the generation of exhausted CD8 + T cell subpopulations and restrains tumor immunity

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          Abstract

          CD8 + T cell exhaustion is a state of dysfunction acquired in chronic viral infection and cancer, characterized by the formation of Slamf6 + progenitor exhausted and Tim-3 + terminally exhausted subpopulations through unknown mechanisms. Here we establish the phosphatase PTPN2 as a novel regulator of the differentiation of the terminally exhausted subpopulation that functions by attenuating type 1 interferon signaling. Deletion of Ptpn2 in CD8 + T cells increased the generation, proliferative capacity, and cytotoxicity of Tim-3 + cells without altering Slamf6 + numbers during LCMV Clone 13 infection. Likewise , Ptpn2-deletion in CD8 + T cells enhanced Tim-3 + anti-tumor responses and improved tumor control. Deletion of Ptpn2 throughout the immune system resulted in MC38 tumor clearance and improved PD-1 checkpoint blockade responses to B16 tumors. Our results indicate that increasing the number of cytotoxic Tim-3 + CD8 + T cells can promote effective anti-tumor immunity and implicate PTPN2 in immune cells as an attractive cancer immunotherapy target.

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          Most cited references23

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          Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade.

          Blocking Programmed Death-1 (PD-1) can reinvigorate exhausted CD8 T cells (TEX) and improve control of chronic infections and cancer. However, whether blocking PD-1 can reprogram TEX into durable memory T cells (TMEM) is unclear. We found that reinvigoration of TEX in mice by PD-L1 blockade caused minimal memory development. After blockade, reinvigorated TEX became reexhausted if antigen concentration remained high and failed to become TMEM upon antigen clearance. TEX acquired an epigenetic profile distinct from that of effector T cells (TEFF) and TMEM cells that was minimally remodeled after PD-L1 blockade. This finding suggests that TEX are a distinct lineage of CD8 T cells. Nevertheless, PD-1 pathway blockade resulted in transcriptional rewiring and reengagement of effector circuitry in the TEX epigenetic landscape. These data indicate that epigenetic fate inflexibility may limit current immunotherapies.
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            Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy.

            Preexisting lymphocytic infiltration of tumors is associated with superior prognostic outcomes in a variety of cancers. Recent studies also suggest that lymphocytic responses may identify patients more likely to benefit from therapies targeting immune checkpoints, suggesting that therapeutic efficacy of immune checkpoint blockade can be enhanced through strategies that induce tumor inflammation. To achieve this effect, we explored the immunotherapeutic potential of oncolytic Newcastle disease virus (NDV). We find that localized intratumoral therapy of B16 melanoma with NDV induces inflammatory responses, leading to lymphocytic infiltrates and antitumor effect in distant (nonvirally injected) tumors without distant virus spread. The inflammatory effect coincided with distant tumor infiltration with tumor-specific CD4(+) and CD8(+) T cells, which was dependent on the identity of the virus-injected tumor. Combination therapy with localized NDV and systemic CTLA-4 blockade led to rejection of preestablished distant tumors and protection from tumor rechallenge in poorly immunogenic tumor models, irrespective of tumor cell line sensitivity to NDV-mediated lysis. Therapeutic effect was associated with marked distant tumor infiltration with activated CD8(+) and CD4(+) effector but not regulatory T cells, and was dependent on CD8(+) cells, natural killer cells, and type I interferon. Our findings demonstrate that localized therapy with oncolytic NDV induces inflammatory immune infiltrates in distant tumors, making them susceptible to systemic therapy with immunomodulatory antibodies, which provides a strong rationale for investigation of such combination therapies in the clinic.
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              Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment.

              Chronic viral infections often result in ineffective CD8 T-cell responses due to functional exhaustion or physical deletion of virus-specific T cells. However, how persisting virus impacts various CD8 T-cell effector functions and influences other aspects of CD8 T-cell dynamics, such as immunodominance and tissue distribution, remains largely unknown. Using different strains of lymphocytic choriomeningitis virus (LCMV), we compared responses to the same CD8 T-cell epitopes during acute or chronic infection. Persistent infection led to a disruption of the normal immunodominance hierarchy of CD8 T-cell responses seen following acute infection and dramatically altered the tissue distribution of LCMV-specific CD8 T cells in lymphoid and nonlymphoid tissues. Most importantly, CD8 T-cell functional impairment occurred in a hierarchical fashion in chronically infected mice. Production of interleukin 2 and the ability to lyse target cells in vitro were the first functions compromised, followed by the ability to make tumor necrosis factor alpha, while gamma interferon production was most resistant to functional exhaustion. Antigen appeared to be the driving force for this loss of function, since a strong correlation existed between the viral load and the level of exhaustion. Further, epitopes presented at higher levels in vivo resulted in physical deletion, while those presented at lower levels induced functional exhaustion. A model is proposed in which antigen levels drive the hierarchical loss of different CD8 T-cell effector functions during chronic infection, leading to distinct stages of functional impairment and eventually to physical deletion of virus-specific T cells. These results have implications for the study of human chronic infections, where similar T-cell deletion and functional dysregulation has been observed.
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                Author and article information

                Journal
                100941354
                21750
                Nat Immunol
                Nat. Immunol.
                Nature immunology
                1529-2908
                1529-2916
                6 August 2019
                16 September 2019
                October 2019
                16 March 2020
                : 20
                : 10
                : 1335-1347
                Affiliations
                [1 ]Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts, 02115, USA
                [2 ]Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, 02115, USA
                [3 ]Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, Massachusetts, 02115, USA
                [4 ]Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts, 02115, USA
                [5 ]Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA
                [6 ]Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, 02115, USA
                [7 ]Senior author
                Author notes

                Author Contributions

                M.W.L., W.N.H., and A.H.S. conceived the project and wrote the manuscript with assistance from T.H.N., M.A.C., B.C.M., E.F.G., J.E.G., and G.J.F.; M.W.L., T.H.N., W.N.H., and A.H.S. designed experiments; M.W.L. and T.H.N. performed and analyzed all experiments with assistance from M.A.C., J.E.G., and E.F.G.; K.B.Y. performed bulk RNA-seq sample processing and analyzed the RNA-seq data; B.C.M. and R.A. performed 10× single-cell RNA-seq sample processing and analyzed the single-cell RNA-seq data; D.R.S. performed ATAC-seq sample processing and analyzed the ATAC-seq data; G.J.F. contributed to αPD-1 experiments.

                Article
                NIHMS1535977
                10.1038/s41590-019-0480-4
                6754306
                31527834
                a214e684-28dd-40e6-a525-d5e7c3776431

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                Immunology
                Immunology

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