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      The Tumor Microenvironment: A Milieu Hindering and Obstructing Antitumor Immune Responses

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          Abstract

          The success of cancer immunotherapy relies on the knowledge of the tumor microenvironment and the immune evasion mechanisms in which the tumor, stroma, and infiltrating immune cells function in a complex network. The potential barriers that profoundly challenge the overall clinical outcome of promising therapies need to be fully identified and counteracted. Although cancer immunotherapy has increasingly been applied, we are far from understanding how to utilize different strategies in the best way and how to combine therapeutic options to optimize clinical benefit. This review intends to give a contemporary and detailed overview of the different roles of immune cells, exosomes, and molecules acting in the tumor microenvironment and how they relate to immune activation and escape. Further, current and novel immunotherapeutic options will be discussed.

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          Most cited references169

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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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            IDO in the Tumor Microenvironment: Inflammation, Counter-Regulation, and Tolerance.

            Indoleamine 2,3-dioxygenase (IDO) has immunoregulatory roles associated with tryptophan metabolism. These include counter-regulation (controlling inflammation) and acquired tolerance in T cells. Recent findings reveal that IDO can be triggered by innate responses during tumorigenesis, and also by attempted T cell activation, either spontaneous or due to immunotherapy. Here we review the current understanding of mechanisms by which IDO participates in the control of inflammation and in peripheral tolerance. Focusing on the tumor microenvironment, we examine the role of IDO in response to apoptotic cells and the impact of IDO on Treg cell function. We discuss how the counter-regulatory and tolerogenic functions of IDO can be targeted for cancer immunotherapy and present an overview of the current clinical progress in this area.
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              Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells.

              Myeloid-derived suppressor cells (MDSCs) have been identified in humans and mice as a population of immature myeloid cells with the ability to suppress T cell activation. They accumulate in tumor-bearing mice and humans and have been shown to contribute to cancer development. Here, we have isolated tumor-derived exosomes (TDEs) from mouse cell lines and shown that an interaction between TDE-associated Hsp72 and MDSCs determines the suppressive activity of the MDSCs via activation of Stat3. In addition, tumor-derived soluble factors triggered MDSC expansion via activation of Erk. TDE-associated Hsp72 triggered Stat3 activation in MDSCs in a TLR2/MyD88-dependent manner through autocrine production of IL-6. Importantly, decreasing exosome production using dimethyl amiloride enhanced the in vivo antitumor efficacy of the chemotherapeutic drug cyclophosphamide in 3 different mouse tumor models. We also demonstrated that this mechanism is relevant in cancer patients, as TDEs from a human tumor cell line activated human MDSCs and triggered their suppressive function in an Hsp72/TLR2-dependent manner. Further, MDSCs from cancer patients treated with amiloride, a drug used to treat high blood pressure that also inhibits exosome formation, exhibited reduced suppressor functions. Collectively, our findings show in both mice and humans that Hsp72 expressed at the surface of TDEs restrains tumor immune surveillance by promoting MDSC suppressive functions.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                15 May 2020
                2020
                : 11
                : 940
                Affiliations
                [1] 1Department of Immunology, Genetics and Pathology, Uppsala University , Uppsala, Sweden
                [2] 2Department of Molecular Biology, Umeå University , Umeå, Sweden
                Author notes

                Edited by: Fabrizio Mattei, Istituto Superiore di Sanità (ISS), Italy

                Reviewed by: Salem Chouaib, Institut Gustave Roussy, France; Luis De La Cruz-Merino, Hospital Universitario Virgen Macarena, Spain

                *Correspondence: Alireza Labani-Motlagh alireza.labani@ 123456igp.uu.se

                This article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2020.00940
                7243284
                32499786
                3c5137f8-9f0a-4cf1-858a-40b8318d24e1
                Copyright © 2020 Labani-Motlagh, Ashja-Mahdavi and Loskog.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 09 January 2020
                : 22 April 2020
                Page count
                Figures: 3, Tables: 1, Equations: 0, References: 282, Pages: 22, Words: 19497
                Categories
                Immunology
                Review

                Immunology
                tumor,tumor microenvironment,immune cells,immune response,immunosuppression,antitumor
                Immunology
                tumor, tumor microenvironment, immune cells, immune response, immunosuppression, antitumor

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