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      γδ T cells in cancer: a small population of lymphocytes with big implications

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          Abstract

          γδ T cells are a small population of mostly tissue‐resident lymphocytes, with both innate and adaptive properties. These unique features make them particularly attractive candidates for the development of new cellular therapy targeted against tumor development. Nevertheless, γδ T cells may play dual roles in cancer, promoting cancer development on the one hand, while participating in antitumor immunity on the other hand. In mice, γδ T‐cell subsets preferentially produce IL‐17 or IFN‐γ. While antitumor functions of murine γδ T cells can be attributed to IFN‐γ + γδ T cells, recent studies have implicated IL‐17 + γδ T cells in tumor growth and metastasis. However, in humans, IL‐17‐producing γδ T cells are rare and most studies have attributed a protective role to γδ T cells against cancer. In this review, we will present the current knowledge and most recent findings on γδ T‐cell functions in mouse models of tumor development and human cancers. We will also discuss their potential as cellular immunotherapy against cancer.

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          Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA.

          Stress-inducible MICA, a distant homolog of major histocompatibility complex (MHC) class I, functions as an antigen for gammadelta T cells and is frequently expressed in epithelial tumors. A receptor for MICA was detected on most gammadelta T cells, CD8+ alphabeta T cells, and natural killer (NK) cells and was identified as NKG2D. Effector cells from all these subsets could be stimulated by ligation of NKG2D. Engagement of NKG2D activated cytolytic responses of gammadelta T cells and NK cells against transfectants and epithelial tumor cells expressing MICA. These results define an activating immunoreceptor-MHC ligand interaction that may promote antitumor NK and T cell responses.
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            Interferon-Gamma at the Crossroads of Tumor Immune Surveillance or Evasion

            Interferon-gamma (IFN-γ) is a pleiotropic molecule with associated antiproliferative, pro-apoptotic and antitumor mechanisms. This effector cytokine, often considered as a major effector of immunity, has been used in the treatment of several diseases, despite its adverse effects. Although broad evidence implicating IFN-γ in tumor immune surveillance, IFN-γ-based therapies undergoing clinical trials have been of limited success. In fact, recent reports suggested that it may also play a protumorigenic role, namely, through IFN-γ signaling insensitivity, downregulation of major histocompatibility complexes, and upregulation of indoleamine 2,3-dioxygenase and of checkpoint inhibitors, as programmed cell-death ligand 1. However, the IFN-γ-mediated responses are still positively associated with patient’s survival in several cancers. Consequently, major research efforts are required to understand the immune contexture in which IFN-γ induces its intricate and highly regulated effects in the tumor microenvironment. This review discusses the current knowledge on the pro- and antitumorigenic effects of IFN-γ as part of the complex immune response to cancer, highlighting the relevance to identify IFN-γ responsive patients for the improvement of therapies that exploit associated signaling pathways.
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              Mechanisms of resistance to CAR T cell therapy

              The successes with chimeric antigen receptor (CAR) T cell therapy in early clinical trials involving patients with pre-B cell acute lymphoblastic leukaemia (ALL) or B cell lymphomas have revolutionized anticancer therapy, providing a potentially curative option for patients who are refractory to standard treatments. These trials resulted in rapid FDA approvals of anti-CD19 CAR T cell products for both ALL and certain types of B cell lymphoma - the first approved gene therapies in the USA. However, growing experience with these agents has revealed that remissions will be brief in a substantial number of patients owing to poor CAR T cell persistence and/or cancer cell resistance resulting from antigen loss or modulation. Furthermore, the initial experience with CAR T cells has highlighted challenges associated with manufacturing a patient-specific therapy. Understanding the limitations of CAR T cell therapy will be critical to realizing the full potential of this novel treatment approach. Herein, we discuss the factors that can preclude durable remissions following CAR T cell therapy, with a primary focus on the resistance mechanisms that underlie disease relapse. We also provide an overview of potential strategies to overcome these obstacles in an effort to more effectively incorporate this unique therapeutic strategy into standard treatment paradigms.
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                Author and article information

                Contributors
                lynchl3@tcd.ie
                Journal
                Clin Transl Immunology
                Clin Transl Immunology
                10.1002/(ISSN)2050-0068
                CTI2
                Clinical & Translational Immunology
                John Wiley and Sons Inc. (Hoboken )
                2050-0068
                10 October 2019
                2019
                : 8
                : 10 ( doiID: 10.1002/cti2.2019.8.issue-10 )
                : e01080
                Affiliations
                [ 1 ] School of Biochemistry and Immunology Trinity College Dublin Dublin Ireland
                [ 2 ] Harvard Medical School Boston MA USA
                [ 3 ] Brigham and Women's Hospital Boston MA USA
                Author notes
                [*] [* ] Correspondence

                L Lynch, School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland.

                E‐mail: lynchl3@ 123456tcd.ie

                Author information
                https://orcid.org/0000-0002-6088-6902
                Article
                CTI21080
                10.1002/cti2.1080
                6787154
                31624593
                f93d9d18-6ef8-42a8-8d95-dbda76592e2f
                © 2019 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology Inc.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 22 April 2019
                : 02 September 2019
                : 02 September 2019
                Page count
                Figures: 2, Tables: 2, Pages: 15, Words: 10887
                Funding
                Funded by: Science Foundation Ireland
                Award ID: #16/FRL/3865
                Funded by: European Research Council
                Award ID: 679173
                Categories
                Special Feature Review
                Special Feature Reviews
                Custom metadata
                2.0
                cti21080
                2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.7.0 mode:remove_FC converted:11.10.2019

                antitumor immunity,car t‐cells,dot cells,immunotherapy,tumor progression,γδ t cells

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