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      Vaccine Strategies to Improve Anti-cancer Cellular Immune Responses

      review-article
      *
      Frontiers in Immunology
      Frontiers Media S.A.
      cancer vaccine, adjuvant, dendritic cell, TLR, STING, checkpoint

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          Abstract

          More than many other fields in medicine, cancer vaccine development has been plagued by a wide gap between the massive amounts of highly encouraging preclinical data on one hand, and the disappointing clinical results on the other. It is clear now that traditional approaches from the infectious diseases' vaccine field cannot be borrowed as such to treat cancer. This review highlights some of the strategies developed to improve vaccine formulations for oncology, including research into more powerful or “smarter” adjuvants to elicit anti-tumoral cellular immune responses. As an illustration of the difficulties in translating smart preclinical strategies into real benefit for the cancer patient, the difficult road of vaccine development in lung cancer is given as example. Finally, an outline is provided of the combinatorial strategies that leverage the increasing knowledge on tumor-associated immune suppressive networks. Indeed, combining with drugs that target the dominant immunosuppressive pathway in a given tumor promises to unlock the true power of cancer vaccines and potentially offer long-term protection from disease relapse.

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          Most cited references96

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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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            Cancer immunotherapy. A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells.

            T cell immunity directed against tumor-encoded amino acid substitutions occurs in some melanoma patients. This implicates missense mutations as a source of patient-specific neoantigens. However, a systematic evaluation of these putative neoantigens as targets of antitumor immunity is lacking. Moreover, it remains unknown whether vaccination can augment such responses. We found that a dendritic cell vaccine led to an increase in naturally occurring neoantigen-specific immunity and revealed previously undetected human leukocyte antigen (HLA) class I-restricted neoantigens in patients with advanced melanoma. The presentation of neoantigens by HLA-A*02:01 in human melanoma was confirmed by mass spectrometry. Vaccination promoted a diverse neoantigen-specific T cell receptor (TCR) repertoire in terms of both TCR-β usage and clonal composition. Our results demonstrate that vaccination directed at tumor-encoded amino acid substitutions broadens the antigenic breadth and clonal diversity of antitumor immunity.
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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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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                22 January 2019
                2019
                : 10
                : 8
                Affiliations
                Tumor Immunology Laboratory, Department of Pulmonary Medicine and Immuno-Oncology Network Ghent, Ghent University Hospital , Ghent, Belgium
                Author notes

                Edited by: An Maria Theophiel Van Nuffel, Anticancer Fund, Belgium

                Reviewed by: Behjatolah Monzavi-Karbassi, University of Arkansas for Medical Sciences, United States; Jan Dörrie, University Hospital Erlangen, Germany

                *Correspondence: Karim Vermaelen karim.vermaelen@ 123456ugent.be

                This article was submitted to Vaccines and Molecular Therapeutics, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2019.00008
                6349827
                30723469
                e4f1ffb3-5ab1-4d02-8f27-811caae70733
                Copyright © 2019 Vermaelen.

                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
                : 07 August 2018
                : 03 January 2019
                Page count
                Figures: 1, Tables: 1, Equations: 0, References: 123, Pages: 17, Words: 13695
                Categories
                Immunology
                Review

                Immunology
                cancer vaccine,adjuvant,dendritic cell,tlr,sting,checkpoint
                Immunology
                cancer vaccine, adjuvant, dendritic cell, tlr, sting, checkpoint

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