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      Identifying baseline immune-related biomarkers to predict clinical outcome of immunotherapy

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          Abstract

          As cancer strikes, individuals vary not only in terms of factors that contribute to its occurrence and development, but as importantly, in their capacity to respond to treatment. While exciting new therapeutic options that mobilize the immune system against cancer have led to breakthroughs for a variety of malignancies, success is limited to a subset of patients. Pre-existing immunological features of both the host and the tumor may contribute to how patients will eventually fare with immunotherapy. A broad understanding of baseline immunity, both in the periphery and in the tumor microenvironment, is needed in order to fully realize the potential of cancer immunotherapy. Such interrogation of the tumor, blood, and host immune parameters prior to treatment is expected to identify biomarkers predictive of clinical outcome as well as to elucidate why some patients fail to respond to immunotherapy. To approach these opportunities for progress, the Society for Immunotherapy of Cancer (SITC) reconvened the Immune Biomarkers Task Force. Comprised of an international multidisciplinary panel of experts, Working Group 4 sought to make recommendations that focus on the complexity of the tumor microenvironment, with its diversity of immune genes, proteins, cells, and pathways naturally present at baseline and in circulation, and novel tools to aid in such broad analyses.

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          Most cited references94

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          Tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2-positive and triple-negative primary breast cancers.

          Modulation of immunologic interactions in cancer tissue is a promising therapeutic strategy. To investigate the immunogenicity of human epidermal growth factor receptor 2 (HER2) -positive and triple-negative (TN) breast cancers (BCs), we evaluated tumor-infiltrating lymphocytes (TILs) and immunologically relevant genes in the neoadjuvant GeparSixto trial.
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            Cytokine patterns in patients with cancer: a systematic review.

            Active, but dysfunctional, immune responses in patients with cancer have been studied in several tumour types, but owing to the heterogeneity of cancer theories of common reaction mechanisms seem to be obsolete. In this Review of published clinical studies of patients with cancer, expression and interplay of the following cytokines are examined: interleukin 2, interleukin 6, interleukin 8, interleukin 10, interleukin 12, interleukin 18, tumour necrosis factor α (TNFα), transforming growth factor β (TGFβ), interferon-γ, HLA-DR, macrophage migration inhibitory factor (MIF), and C-X-C motif chemokine receptor 4 (CXCR4). Clinical data were analysed in a non-quantitative descriptive manner and interpreted with regard to experimentally established physiological cytokine interactions. The clinical cytokine pattern that emerged suggests that simultaneous immunostimulation and immunosuppression occur in patients with cancer, with increased concentrations of the cytokines MIF, TNFα, interleukin 6, interleukin 8, interleukin 10, interleukin 18, and TGFβ. This specific cytokine pattern seems to have a prognostic effect, since high interleukin 6 or interleukin 10 serum concentrations are associated with negative prognoses in independent cancer types. Although immunostimulatory cytokines are involved in local cancer-associated inflammation, cancer cells seem to be protected from immunological eradication by cytokine-mediated local immunosuppression and a resulting defect of the interleukin 12-interferon-γ-HLA-DR axis. Cytokines produced by tumours might have a pivotal role in this defect. A working hypothesis is that the cancer-specific and histology-independent uniform cytokine cascade is one of the manifestations of the underlying paraneoplastic systemic disease, and this hypothesis links the stage of cancer with both the functional status of the immune system and the patient's prognosis. Neutralisation of this cytokine pattern could offer novel and so far unexploited treatment approaches for cancer. Copyright © 2013 Elsevier Ltd. All rights reserved.
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              The Next Hurdle in Cancer Immunotherapy: Overcoming the Non-T-Cell-Inflamed Tumor Microenvironment.

              A growing body of evidence suggests that a major subset of patients with advanced solid tumors shows evidence for a T-cell-inflamed tumor microenvironment. This phenotype has positive prognostic value for several types of early stage cancer, suggesting that the attempt by the host to generate an anti-tumor immune response reflects a biologic process associated with improved patient outcomes. In metastatic disease, the presence of this phenotype appears to be associated with clinical response to several immunotherapies, including cancer vaccines, checkpoint blockade, and adoptive T-cell transfer. With the high rate of clinical response to several of these therapies, along with early data indicating that combination immunotherapies may be even more potent, it seems likely that effective immune-based therapies will become a reality for patients with a range of different cancers that physiologically support the T-cell-inflamed tumor microenvironment in a subset of individuals. Therefore, one of the next significant hurdles will be to develop new therapeutic interventions that will enable these immunotherapies to be effective in patients with the non-T-cell-inflamed phenotype. Rational development of such interventions will benefit from a detailed molecular understanding of the mechanisms that explain the presence or absence of the T-cell-inflamed tumor microenvironment, which in turn will benefit from focused interrogation of patient samples. This iterative "reverse-translational" research strategy has already identified new candidate therapeutic targets and approaches. It is envisioned that the end result of these investigations will be an expanded array of interventions that will broaden the fraction of patients benefitting from immunotherapies in the clinic.
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                Author and article information

                Contributors
                sacha.gnjatic@mssm.edu
                vincenzo.bronte@univr.it
                lrb@immodulon.com
                Marcus.Butler@uhn.ca
                ndisis@uw.edu
                jerome.galon@crc.jussieu.fr
                canimguide@gmail.com
                brent.hanks@duke.edu
                vaios.karanikas@roche.com
                skhleif@gru.edu
                kirkwoodjm@upmc.edu
                ldmiller@wakehealth.edu
                d.schendel@medigene.com
                itanneau@yahoo.fr
                wiggintonj@macrogenics.com
                butterfieldl@upmc.edu
                Journal
                J Immunother Cancer
                J Immunother Cancer
                Journal for Immunotherapy of Cancer
                BioMed Central (London )
                2051-1426
                16 May 2017
                16 May 2017
                2017
                : 5
                : 44
                Affiliations
                [1 ]ISNI 0000 0001 0670 2351, GRID grid.59734.3c, , Department of Hematology/Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, ; S5-105, 1470 Madison Avenue, Box 1128, New York, NY 10029 USA
                [2 ]ISNI 0000 0004 1763 1124, GRID grid.5611.3, Head of Immunology Section, , University of Verona, ; Piazzale Le L. A. Scuro, 10, Verona, Italy
                [3 ]GRID grid.476398.7, , Immodulon Therapeutics Ltd, ; Stockley Park, 6-9 The Square, Uxbridge, UK
                [4 ]ISNI 0000 0001 2150 066X, GRID grid.415224.4, , Princess Margaret Hospital/Ontario Cancer Institute, ; RM 9-622, 610 University Ave, Toronto, ON Canada
                [5 ]ISNI 0000000122986657, GRID grid.34477.33, , University of Washington, Tumor Vaccine Group, ; 850 Mercer Street, Box 358050, Seattle, WA 98109 USA
                [6 ]GRID grid.462406.2, , INSERM - Cordeliers Research Center, Integrative Cancer Immunology Laboratory, ; 15 rue de l’Ecole de Médecine, Paris, France
                [7 ]CanImGuide Therapeutics AB, Domkyrkovägen 23, Hoellviken, Sweden
                [8 ]ISNI 0000000100241216, GRID grid.189509.c, , Duke University Medical Center, ; 308 Research Drive, LSRC, Room C203, Box 3819, Durham, NC 27708 USA
                [9 ]Roche Innovation Center Zurich, Wagistrasse 18, Schlieren, Switzerland
                [10 ]ISNI 0000 0001 2284 9329, GRID grid.410427.4, Georgia Cancer Center, , Augusta University, ; 1120 15th Street, CN-2101A, Augusta, GA 30912 USA
                [11 ]ISNI 0000 0004 1936 9000, GRID grid.21925.3d, , University of Pittsburgh, Hillman Cancer Center-Research Pavilion, ; 5117 Centre Avenue, Suite 1.32, Pittsburg, PA 15213 USA
                [12 ]ISNI 0000 0001 2185 3318, GRID grid.241167.7, , Wake Forest School of Medicine, ; 1 Medical Center Blvd, Winston Salem, NC 27157 USA
                [13 ]Medigene Immunotherapies GmbH, Lochhamer Strasse 11, Planegg-Martinsried, Germany
                [14 ]ImmunID, 7 Parvis Louis Néel, BP50 Grenoble, France
                [15 ]ISNI 0000 0004 0432 6278, GRID grid.421076.6, , MacroGenics, Inc., ; 9704 Medical Center Drive, Rockville, MD 20850 USA
                [16 ]ISNI 0000 0004 0456 9819, GRID grid.478063.e, Department of Medicine, Surgery and Immunology, , University of Pittsburgh Cancer Institute, ; 5117 Centre Avenue, Pittsburgh, PA 15213 USA
                Article
                243
                10.1186/s40425-017-0243-4
                5432988
                28515944
                a7865e42-193d-47bf-a2bd-8e3f165298b5
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 17 November 2016
                : 26 April 2017
                Categories
                Review
                Custom metadata
                © The Author(s) 2017

                cancer immunotherapy,tumor microenvironment,biomarkers,baseline immunity,immune checkpoint inhibitors

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