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      Interferon-Gamma at the Crossroads of Tumor Immune Surveillance or Evasion

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          Abstract

          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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          A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17.

          Interleukin 17 (IL-17) has been linked to autoimmune diseases, although its regulation and function have remained unclear. Here we have evaluated in vitro and in vivo the requirements for the differentiation of naive CD4 T cells into effector T helper cells that produce IL-17. This process required the costimulatory molecules CD28 and ICOS but was independent of the cytokines and transcription factors required for T helper type 1 or type 2 differentiation. Furthermore, both IL-4 and interferon-gamma negatively regulated T helper cell production of IL-17 in the effector phase. In vivo, antibody to IL-17 inhibited chemokine expression in the brain during experimental autoimmune encephalomyelitis, whereas overexpression of IL-17 in lung epithelium caused chemokine production and leukocyte infiltration. Thus, IL-17 expression characterizes a unique T helper lineage that regulates tissue inflammation.
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            The immune contexture in cancer prognosis and treatment

            Immunotherapy is currently the most rapidly advancing area of clinical oncology, and provides the unprecedented opportunity to effectively treat, and even cure, several previously untreatable malignancies. A growing awareness exists of the fact that the success of chemotherapy and radiotherapy, in which the patient's disease can be stabilized well beyond discontinuation of treatment (and occasionally is cured), also relies on the induction of a durable anticancer immune response. Indeed, the local immune infiltrate undergoes dynamic changes that accompany a shift from a pre-existing immune response to a therapy-induced immune response. As a result, the immune contexture, which is determined by the density, composition, functional state and organization of the leukocyte infiltrate of the tumour, can yield information that is relevant to prognosis, prediction of a treatment response and various other pharmacodynamic parameters. Several complementary technologies can be used to explore the immune contexture of tumours, and to derive biomarkers that could enable the adaptation of individual treatment approaches for each patient, as well as monitoring a response to anticancer therapies.
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              IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity.

              Lymphocytes were originally thought to form the basis of a 'cancer immunosurveillance' process that protects immunocompetent hosts against primary tumour development, but this idea was largely abandoned when no differences in primary tumour development were found between athymic nude mice and syngeneic wild-type mice. However, subsequent observations that nude mice do not completely lack functional T cells and that two components of the immune system-IFNgamma and perforin-help to prevent tumour formation in mice have led to renewed interest in a tumour-suppressor role for the immune response. Here we show that lymphocytes and IFNgamma collaborate to protect against development of carcinogen-induced sarcomas and spontaneous epithelial carcinomas and also to select for tumour cells with reduced immunogenicity. The immune response thus functions as an effective extrinsic tumour-suppressor system. However, this process also leads to the immunoselection of tumour cells that are more capable of surviving in an immunocompetent host, which explains the apparent paradox of tumour formation in immunologically intact individuals.
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                Author and article information

                Contributors
                URI : https://frontiersin.org/people/u/410570
                URI : https://frontiersin.org/people/u/506288
                URI : https://frontiersin.org/people/u/120366
                URI : https://frontiersin.org/people/u/131294
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                04 May 2018
                2018
                : 9
                : 847
                Affiliations
                [1] 1i3S – Instituto de Investigação e Inovação em Saúde, Universidade do Porto , Porto, Portugal
                [2] 2INEB – Instituto de Engenharia Biomédica, Universidade do Porto , Porto, Portugal
                [3] 3ICBAS – Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto , Porto, Portugal
                [4] 4IMM – Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa , Lisbon, Portugal
                [5] 5Departamento de Patologia e Oncologia, Faculdade de Medicina, Universidade do Porto , Porto, Portugal
                Author notes

                Edited by: Fabrizio Mattei, Istituto Superiore di Sanità, Italy

                Reviewed by: Alexandre Corthay, Oslo University Hospital, Norway; Christine Susanne Falk, Hannover Medical School, Germany

                *Correspondence: Maria José Oliveira, mariajo@ 123456ineb.up.pt

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

                Article
                10.3389/fimmu.2018.00847
                5945880
                29780381
                e34b0d57-a181-4793-b620-f895f2ed2715
                Copyright © 2018 Castro, Cardoso, Gonçalves, Serre and Oliveira.

                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 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
                : 06 December 2017
                : 05 April 2018
                Page count
                Figures: 4, Tables: 1, Equations: 0, References: 308, Pages: 19, Words: 17770
                Funding
                Funded by: European Regional Development Fund 10.13039/501100008530
                Award ID: COMPETE 2020—Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020
                Funded by: Fundação para a Ciência e a Tecnologia 10.13039/501100001871
                Award ID: POCI-01-0145-FEDER-007274, PD/BD/114013/2015, IF/00638/2014, IF/00004/2014 IF/01066/2012, and, POCI-01-0145-FEDER-016390
                Categories
                Immunology
                Review

                Immunology
                type ii interferon,immunoregulation,cancer microenvironment,immunotherapy,immune contexture

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