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      TIM3 +FOXP3 + regulatory T cells are tissue-specific promoters of T-cell dysfunction in cancer

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          Abstract

          T-cell immunoglobulin mucin 3 (TIM3) is an inhibitory molecule that has emerged as a key regulator of dysfunctional or exhausted CD8 + T cells arising in chronic diseases such as cancer. In addition to exhausted CD8 + T cells, highly suppressive regulatory T cells (Tregs) represent a significant barrier against the induction of antitumor immunity. We have found that the majority of intratumoral FOXP3 + Tregs express TIM3. TIM3 + Tregs co-express PD-1, are highly suppressive and comprise a specialized subset of tissue Tregs that are rarely observed in the peripheral tissues or blood of tumor-bearing mice. The co-blockade of the TIM3 and PD-1 signaling pathways in vivo results in the downregulation of molecules associated with TIM3 + Treg suppressor functions. This suggests that the potent clinical efficacy of co-blocking TIM3 and PD-1 signal transduction cascades likely stems from the reversal of T-cell exhaustion combined with the inhibition of regulatory T-cell function in tumor tissues. Interestingly, we find that TIM3 + Tregs accumulate in the tumor tissue prior to the appearance of exhausted CD8 + T cells, and that the depletion of Tregs at this stage interferes with the development of the exhausted phenotype by CD8 + T cells. Collectively, our data indicate that TIM3 marks highly suppressive tissue-resident Tregs that play an important role in shaping the antitumor immune response in situ, increasing the value of TIM3-targeting therapeutic strategies against cancer.

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          Most cited references18

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          Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease.

          Activation of naive CD4(+) T-helper cells results in the development of at least two distinct effector populations, Th1 and Th2 cells. Th1 cells produce cytokines (interferon (IFN)-gamma, interleukin (IL)-2, tumour-necrosis factor (TNF)-alpha and lymphotoxin) that are commonly associated with cell-mediated immune responses against intracellular pathogens, delayed-type hypersensitivity reactions, and induction of organ-specific autoimmune diseases. Th2 cells produce cytokines (IL-4, IL-10 and IL-13) that are crucial for control of extracellular helminthic infections and promote atopic and allergic diseases. Although much is known about the functions of these two subsets of T-helper cells, there are few known surface molecules that distinguish between them. We report here the identification and characterization of a transmembrane protein, Tim-3, which contains an immunoglobulin and a mucin-like domain and is expressed on differentiated Th1 cells. In vivo administration of antibody to Tim-3 enhances the clinical and pathological severity of experimental autoimmune encephalomyelitis (EAE), a Th1-dependent autoimmune disease, and increases the number and activation level of macrophages. Tim-3 may have an important role in the induction of autoimmune diseases by regulating macrophage activation and/or function.
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            Anti-TIM3 antibody promotes T cell IFN-γ-mediated antitumor immunity and suppresses established tumors.

            Strategies to activate and rescue exhausted tumor-specific T cells, including the use of monoclonal antibodies (mAb) that block the negative costimulatory receptors CTLA-4 and PD-1 are proving very effective, but TIM3 has been relatively neglected as a target. Here we report an extensive characterization of the therapeutic activity and mechanism of action of an anti-mouse TIM3 mAb against experimental and carcinogen-induced tumors. For the first time we specifically define the mechanism of antitumor action of anti-TIM3 requiring IFN-γ producing CD8(+) T cells and CD4(+) T cells, and a higher ratio of tumor infiltrating CD8(+):CD4(+) T cells correlating with therapeutic success. Interestingly, in some models, anti-TIM3 appeared to be effective sometime before the appearance and accumulation of significant TIM3(+)PD-1(+) T cell populations in tumor bearing mice. Anti-TIM3 displayed modest prophylactic and therapeutic activity against a small fraction of carcinogen-induced sarcomas, but comparative and combination studies of anti-TIM3 with anti-CTLA-4 and anti-PD-1 against experimental and carcinogen-induced tumors suggested that these agents might be well-tolerated and very effective in combination. ©2011 AACR
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              Tim-3 inhibits T helper type 1-mediated auto- and alloimmune responses and promotes immunological tolerance.

              Although T helper (T(H)) cell-mediated immunity is required to effectively eliminate pathogens, unrestrained T(H) activity also contributes to tissue injury in many inflammatory and autoimmune diseases. We report here that the T(H) type 1 (T(H)1)-specific Tim-3 (T cell immunoglobulin domain, mucin domain) protein functions to inhibit aggressive T(H)1-mediated auto- and alloimmune responses. Tim-3 pathway blockade accelerated diabetes in nonobese diabetic mice and prevented acquisition of transplantation tolerance induced by costimulation blockade. These effects were mediated, at least in part, by dampening of the antigen-specific immunosuppressive function of CD4(+)CD25(+) regulatory T cell populations. Our data indicate that the Tim-3 pathway provides an important mechanism to down-regulate T(H)1-dependent immune responses and to facilitate the development of immunological tolerance.
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                Author and article information

                Journal
                Oncoimmunology
                Oncoimmunology
                ONCI
                Oncoimmunology
                Landes Bioscience
                2162-4011
                2162-402X
                01 April 2013
                01 April 2013
                01 April 2013
                : 2
                : 4
                : e23849
                Affiliations
                [1 ]Center of Neurologic Diseases; Department of Neurology; Brigham and Women’s Hospital; Harvard Medical School; Boston, MA USA
                [2 ]Cancer Immunology Program; Trescowthick Laboratories; Peter MacCallum Cancer Centre; East Melbourne, VIC Australia
                [3 ]Sir Peter MacCallum Department of Oncology; University of Melbourne; Parkville, VIC Australia
                [4 ]Department of Pathology; University of Melbourne; Parkville, VIC Australia
                Author notes
                [* ]Correspondence to: Ana C. Anderson, Email: aanderson@ 123456rics.bwh.harvard.edu
                Article
                2012ONCOIMM0410R 23849
                10.4161/onci.23849
                3654601
                23734331
                f18becb6-f138-4969-ad68-24a81124c1d9
                Copyright © 2013 Landes Bioscience

                This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.

                History
                : 20 December 2012
                : 31 January 2013
                : 31 January 2013
                Categories
                Research Paper

                Immunology
                antibody,immunotherapy,inhibitory receptor,regulatory t cells,t-cell exhaustion
                Immunology
                antibody, immunotherapy, inhibitory receptor, regulatory t cells, t-cell exhaustion

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