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      Role of Type I and II Interferons in Colorectal Cancer and Melanoma

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          Abstract

          Cancer can be considered an aberrant organ with a hierarchical composition of different cell populations. The tumor microenvironment, including the immune cells and related cytokines, is crucial during all the steps of tumor development. In particular, type I and II interferons (IFNs) are involved in a plethora of mechanisms that regulate immune responses in cancer, thus balancing immune escape versus immune surveillance. IFNs are involved in both the direct and indirect regulation of cancer cell proliferation and metastatic potential. The mutational background of genes involved in IFNs signaling could serve as a prognostic biomarker and a powerful tool to screen cancer patients eligible for checkpoint blocking therapies. We herewith describe the latest findings regarding the contribution of IFNs in colorectal cancer and melanoma by researching their dual role as either tumor promoter or suppressor, in diverse tumor types, and microenvironmental context. We are reporting the most innovative and promising approaches of IFN-based therapies that have achieved considerable outcomes in clinical oncology practice and explain the possible mechanisms responsible for their failure.

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          Most cited references106

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          STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors.

          Spontaneous T cell responses against tumors occur frequently and have prognostic value in patients. The mechanism of innate immune sensing of immunogenic tumors leading to adaptive T cell responses remains undefined, although type I interferons (IFNs) are implicated in this process. We found that spontaneous CD8(+) T cell priming against tumors was defective in mice lacking stimulator of interferon genes complex (STING), but not other innate signaling pathways, suggesting involvement of a cytosolic DNA sensing pathway. In vitro, IFN-? production and dendritic cell activation were triggered by tumor-cell-derived DNA, via cyclic-GMP-AMP synthase (cGAS), STING, and interferon regulatory factor 3 (IRF3). In the tumor microenvironment in vivo, tumor cell DNA was detected within host antigen-presenting cells, which correlated with STING pathway activation and IFN-? production. Our results demonstrate that a major mechanism for innate immune sensing of cancer occurs via the host STING pathway, with major implications for cancer immunotherapy. Copyright © 2014 Elsevier Inc. All rights reserved.
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            LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells.

            Elevated lactate dehydrogenase A (LDHA) expression is associated with poor outcome in tumor patients. Here we show that LDHA-associated lactic acid accumulation in melanomas inhibits tumor surveillance by T and NK cells. In immunocompetent C57BL/6 mice, tumors with reduced lactic acid production (Ldha(low)) developed significantly slower than control tumors and showed increased infiltration with IFN-γ-producing T and NK cells. However, in Rag2(-/-)γc(-/-) mice, lacking lymphocytes and NK cells, and in Ifng(-/-) mice, Ldha(low) and control cells formed tumors at similar rates. Pathophysiological concentrations of lactic acid prevented upregulation of nuclear factor of activated T cells (NFAT) in T and NK cells, resulting in diminished IFN-γ production. Database analyses revealed negative correlations between LDHA expression and T cell activation markers in human melanoma patients. Our results demonstrate that lactic acid is a potent inhibitor of function and survival of T and NK cells leading to tumor immune escape.
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              ONCOLYTIC VIROTHERAPY

              Oncolytic virotherapy is an emerging treatment modality which uses replication competent viruses to destroy cancers. Advances in the past two years include preclinical proof of feasibility for a single-shot virotherapy cure, identification of drugs that accelerate intratumoral virus propagation, new strategies to maximize the immunotherapeutic potential of oncolytic virotherapy, and clinical confirmation of a critical viremic thereshold for vascular delivery and intratumoral virus replication. The primary clinical milestone was completion of accrual in a phase III trial of intratumoral herpes simplex virus therapy using talimogene laherparepvec for metastatic melanoma. Challenges for the field are to select ‘winners’ from a burgeoning number of oncolytic platforms and engineered derivatives, to transiently suppress but then unleash the power of the immune system to maximize both virus spread and anticancer immunity, to develop more meaningful preclinical virotherapy models and to manufacture viruses with orders of magnitude higher yields compared to established vaccine manufacturing processes.
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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
                26 July 2017
                2017
                : 8
                : 878
                Affiliations
                [1] 1Cellular and Molecular Pathophysiology Laboratory, Department of Surgical, Oncological and Stomatological Sciences, University of Palermo , Palermo, Italy
                [2] 2Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), University of Palermo , Palermo, Italy
                [3] 3DiBiMIS, University of Palermo , Palermo, Italy
                Author notes

                Edited by: Matteo Bellone, San Raffaele Hospital (IRCCS), Italy

                Reviewed by: Enrico Proietti, Istituto Superiore di Sanità, Italy; Daniel Olive, Institut national de la santé et de la recherche médicale, France; Leticia Corrales, Aduro BioTech, United States

                *Correspondence: Giorgio Stassi, giorgio.stassi@ 123456unipa.it

                These authors have contributed equally to this work.

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

                Article
                10.3389/fimmu.2017.00878
                5526853
                28798748
                d0a1e869-13f7-4d26-aaea-7ceba4c667af
                Copyright © 2017 Di Franco, Turdo, Todaro and Stassi.

                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) or licensor 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
                : 19 April 2017
                : 10 July 2017
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 134, Pages: 13, Words: 11307
                Funding
                Funded by: Associazione Italiana per la Ricerca sul Cancro 10.13039/501100005010
                Award ID: IG 16746, IG 14415
                Funded by: Ministero della Salute 10.13039/501100003196
                Award ID: RF-2011- 02349126
                Categories
                Immunology
                Review

                Immunology
                interferon,cancer,colon,melanoma,tumor immunology,cancer progression,anti-cancer therapy
                Immunology
                interferon, cancer, colon, melanoma, tumor immunology, cancer progression, anti-cancer therapy

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