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      Long non-coding RNA Lnc-Tim3 exacerbates CD8 T cell exhaustion via binding to Tim-3 and inducing nuclear translocation of Bat3 in HCC

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          Abstract

          Although one of the first comprehensive examinations of long non-coding RNA (lncRNA) expression was performed in human CD8 T lymphocytes, little is known about their roles in CD8 T cells functions during the progression of hepatocellular carcinoma (HCC). Here, we show that Lnc-Tim3 is upregulated and negatively correlates with IFN-γ and IL-2 production in tumor-infiltrating CD8 T cells of HCC patients. Lnc-Tim3 plays a pivotal role in stimulating CD8 T exhaustion and the survival of the exhausted CD8 T cells. Mechanistically, Lnc-Tim3 specifically binds to Tim-3 and blocks its interaction with Bat3, thus suppressing downstream Lck/ NFAT1/AP-1 signaling, leading to nuclear localization of Bat3, and enhancing p300-dependent p53 and RelA transcriptional activation of anti-apoptosis genes including MDM2 and Bcl-2. In summary, Lnc-Tim3 promotes T cell exhaustion, a phenotype which is correlated with compromised anti-tumor immunity, suggesting that Lnc-Tim3 and its associated signaling pathways may influence the outcome of cancer therapies aimed at modulating the acquired immune system.

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          Molecular and cellular insights into T cell exhaustion.

          In chronic infections and cancer, T cells are exposed to persistent antigen and/or inflammatory signals. This scenario is often associated with the deterioration of T cell function: a state called 'exhaustion'. Exhausted T cells lose robust effector functions, express multiple inhibitory receptors and are defined by an altered transcriptional programme. T cell exhaustion is often associated with inefficient control of persisting infections and tumours, but revitalization of exhausted T cells can reinvigorate immunity. Here, we review recent advances that provide a clearer molecular understanding of T cell exhaustion and reveal new therapeutic targets for persisting infections and cancer.
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            Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity

            The immune response plays an important role in staving off cancer; however, mechanisms of immunosuppression hinder productive anti-tumor immunity. T cell dysfunction or exhaustion in tumor-bearing hosts is one such mechanism. PD-1 has been identified as a marker of exhausted T cells in chronic disease states, and blockade of PD-1–PD-1L interactions has been shown to partially restore T cell function. We have found that T cell immunoglobulin mucin (Tim) 3 is expressed on CD8+ tumor-infiltrating lymphocytes (TILs) in mice bearing solid tumors. All Tim-3+ TILs coexpress PD-1, and Tim-3+PD-1+ TILs represent the predominant fraction of T cells infiltrating tumors. Tim-3+PD-1+ TILs exhibit the most severe exhausted phenotype as defined by failure to proliferate and produce IL-2, TNF, and IFN-γ. We further find that combined targeting of the Tim-3 and PD-1 pathways is more effective in controlling tumor growth than targeting either pathway alone.
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              Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation.

              Co-inhibitory receptors, such as CTLA-4 and PD-1, have an important role in regulating T cell responses and have proven to be effective targets in the setting of chronic diseases where constitutive co-inhibitory receptor expression on T cells dampens effector T cell responses. Unfortunately, many patients still fail to respond to therapies that target CTLA-4 and PD-1. The next wave of co-inhibitory receptor targets that are being explored in clinical trials include Lag-3, Tim-3, and TIGIT. These receptors, although they belong to the same class of receptors as PD-1 and CTLA-4, exhibit unique functions, especially at tissue sites where they regulate distinct aspects of immunity. Increased understanding of the specialized functions of these receptors will inform the rational application of therapies that target these receptors to the clinic.
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                Author and article information

                Contributors
                +86-25-68136746 , sunbc@njmu.edu.cn
                Journal
                Cell Death Dis
                Cell Death Dis
                Cell Death & Disease
                Nature Publishing Group UK (London )
                2041-4889
                30 April 2018
                30 April 2018
                May 2018
                : 9
                : 5
                Affiliations
                [1 ]ISNI 0000 0000 9255 8984, GRID grid.89957.3a, Liver Transplantation Center of the First Affiliated Hospital and State Key Laboratory of Reproductive Medicine, , Nanjing Medical University, ; Nanjing, Jiangsu Province China
                [2 ]ISNI 0000 0004 1799 0784, GRID grid.412676.0, Department of Laboratory Medicine, , the First Affiliated Hospital of Nanjing Medical University, ; Nanjing, Jiangsu Province China
                [3 ]GRID grid.452511.6, Department of Gastroenterology, The Second Affiliated Hospital of Nanjing Medical University, ; Nanjing, Jiangsu Province China
                [4 ]ISNI 0000 0000 9255 8984, GRID grid.89957.3a, Department of General Surgery, , The Affiliated Changzhou No.2 People’s Hospital of Nanjing Medical University, ; Nanjing, Jiangsu Province China
                Article
                528
                10.1038/s41419-018-0528-7
                5924754
                29706626
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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                © The Author(s) 2018

                Cell biology

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