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      Fates of CD8+ T cells in Tumor Microenvironment

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          Abstract

          Studies have reported a positive correlation between elevated CD8+ T cells in the tumor microenvironment (TME) and good prognosis in cancer. However, the mechanisms linking T cell tumor-infiltration and tumor rejection are yet to be fully understood. The cells and factors of the TME facilitate tumor development in various ways. CD8+ T cell function is influenced by a number of factors, including CD8+ T cell trafficking and localization into tumor sites; as well as CD8+ T cell growth and differentiation. This review highlights recent literature as well as currently evolving concepts regarding the fates of CD8+ T cells in the TME from three different aspects CD8+ T cell trafficking, differentiation and function. A thorough understanding of factors contributing to the fates of CD8+ T cells will allow researchers to develop new strategies and improve on already existing strategies to facilitate CD8+ T cell mediated anti-tumor function, impede T cell dysfunction and modulate the TME into a less immunosuppressive TME.

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          Most cited references120

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          THE METABOLISM OF TUMORS IN THE BODY

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            LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells.

            Elevated lactate dehydrogenase A (LDHA) expression is associated with poor outcome in tumor patients. Here we show that LDHA-associated lactic acid accumulation in melanomas inhibits tumor surveillance by T and NK cells. In immunocompetent C57BL/6 mice, tumors with reduced lactic acid production (Ldha(low)) developed significantly slower than control tumors and showed increased infiltration with IFN-γ-producing T and NK cells. However, in Rag2(-/-)γc(-/-) mice, lacking lymphocytes and NK cells, and in Ifng(-/-) mice, Ldha(low) and control cells formed tumors at similar rates. Pathophysiological concentrations of lactic acid prevented upregulation of nuclear factor of activated T cells (NFAT) in T and NK cells, resulting in diminished IFN-γ production. Database analyses revealed negative correlations between LDHA expression and T cell activation markers in human melanoma patients. Our results demonstrate that lactic acid is a potent inhibitor of function and survival of T and NK cells leading to tumor immune escape.
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              Regulatory T cells, tumour immunity and immunotherapy.

              Tumours express a range of antigens, including self-antigens. Regulatory T cells are crucial for maintaining T-cell tolerance to self-antigens. Regulatory T cells are thought to dampen T-cell immunity to tumour-associated antigens and to be the main obstacle tempering successful immunotherapy and active vaccination. In this Review, I consider the nature and characteristics of regulatory T cells in the tumour microenvironment and their potential multiple suppressive mechanisms. Strategies for therapeutic targeting of regulatory T cells and the effect of regulatory T cells on current immunotherapeutic and vaccine regimens are discussed.
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                Author and article information

                Contributors
                Journal
                Comput Struct Biotechnol J
                Comput Struct Biotechnol J
                Computational and Structural Biotechnology Journal
                Research Network of Computational and Structural Biotechnology
                2001-0370
                22 November 2018
                2019
                22 November 2018
                : 17
                : 1-13
                Affiliations
                [a ]Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
                [b ]Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
                [c ]Henan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou 450052, China
                Author notes
                [* ]Corresponding author at: Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Zhengzhou, Henan, 450052, China. yizhang@ 123456zzu.edu.cn
                [1]

                These authors contributed equally to this work.

                Article
                S2001-0370(18)30121-1
                10.1016/j.csbj.2018.11.004
                6297055
                30581539
                602e15bf-d743-4ba8-ba63-260b2cf2068f
                © 2018 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 30 August 2018
                : 14 November 2018
                : 18 November 2018
                Categories
                Review Article

                cd8+ t cell fates,tumor microenvironment,cd8+ t cell differentiation,cd8+ t cell trafficking,t cell exhaustion

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