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      Molecular and Translational Classifications of DAMPs in Immunogenic Cell Death

      research-article
      1 , * , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 2 , 3 , 4 , 5 , 6 , 13 , 14 , 15 , 16 , 10 , 11 , 17 , 18 , 19 , 20 , 1 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 15 , 31 , 2 , 3 , 4 , 5 , 32 , 2 , 3 , 4 , 5 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 15 , 42 , 43 , 44 , 45 , 46 , 1 , 1 , 47 , 48 , 49 , 22 , 23 , 50 , 2 , 3 , 4 , 5 , 6 , 35 , 36 , 51 , 52 , 51 , 53 , 6 , 54 , 55 , 56 , 1 , *
      Frontiers in Immunology
      Frontiers Media S.A.
      anti-tumor immunity, immunogenicity, immunotherapy, molecular medicine, oncoimmunology, patient prognosis, translational medicine

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          The immunogenicity of malignant cells has recently been acknowledged as a critical determinant of efficacy in cancer therapy. Thus, besides developing direct immunostimulatory regimens, including dendritic cell-based vaccines, checkpoint-blocking therapies, and adoptive T-cell transfer, researchers have started to focus on the overall immunobiology of neoplastic cells. It is now clear that cancer cells can succumb to some anticancer therapies by undergoing a peculiar form of cell death that is characterized by an increased immunogenic potential, owing to the emission of the so-called “damage-associated molecular patterns” (DAMPs). The emission of DAMPs and other immunostimulatory factors by cells succumbing to immunogenic cell death (ICD) favors the establishment of a productive interface with the immune system. This results in the elicitation of tumor-targeting immune responses associated with the elimination of residual, treatment-resistant cancer cells, as well as with the establishment of immunological memory. Although ICD has been characterized with increased precision since its discovery, several questions remain to be addressed. Here, we summarize and tabulate the main molecular, immunological, preclinical, and clinical aspects of ICD, in an attempt to capture the essence of this phenomenon, and identify future challenges for this rapidly expanding field of investigation.

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          The blockade of immune checkpoints in cancer immunotherapy.

          Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
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            The danger model: a renewed sense of self.

            For over 50 years immunologists have based their thoughts, experiments, and clinical treatments on the idea that the immune system functions by making a distinction between self and nonself. Although this paradigm has often served us well, years of detailed examination have revealed a number of inherent problems. This Viewpoint outlines a model of immunity based on the idea that the immune system is more concerned with entities that do damage than with those that are foreign.
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              Of mice and not men: differences between mouse and human immunology.

              Mice are the experimental tool of choice for the majority of immunologists and the study of their immune responses has yielded tremendous insight into the workings of the human immune system. However, as 65 million years of evolution might suggest, there are significant differences. Here we outline known discrepancies in both innate and adaptive immunity, including: balance of leukocyte subsets, defensins, Toll receptors, inducible NO synthase, the NK inhibitory receptor families Ly49 and KIR, FcR, Ig subsets, the B cell (BLNK, Btk, and lambda5) and T cell (ZAP70 and common gamma-chain) signaling pathway components, Thy-1, gammadelta T cells, cytokines and cytokine receptors, Th1/Th2 differentiation, costimulatory molecule expression and function, Ag-presenting function of endothelial cells, and chemokine and chemokine receptor expression. We also provide examples, such as multiple sclerosis and delayed-type hypersensitivity, where complex multicomponent processes differ. Such differences should be taken into account when using mice as preclinical models of human disease.
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                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                20 November 2015
                2015
                : 6
                : 588
                Affiliations
                [1] 1Cell Death Research and Therapy Laboratory, Department of Cellular Molecular Medicine, KU Leuven – University of Leuven , Leuven, Belgium
                [2] 2Equipe 11 Labellisée Ligue Contre le Cancer, Centre de Recherche des Cordeliers , Paris, France
                [3] 3U1138, INSERM , Paris, France
                [4] 4Université Paris Descartes, Sorbonne Paris Cité , Paris, France
                [5] 5Université Pierre et Marie Curie , Paris, France
                [6] 6Gustave Roussy Comprehensive Cancer Institute , Villejuif, France
                [7] 7U866, INSERM , Dijon, France
                [8] 8Faculté de Médecine, Université de Bourgogne , Dijon, France
                [9] 9Centre Georges François Leclerc , Dijon, France
                [10] 10Department of Gynaecology and Obstetrics, UZ Leuven , Leuven, Belgium
                [11] 11Laboratory of Gynaecologic Oncology, Department of Oncology, Leuven Cancer Institute, KU Leuven , Leuven, Belgium
                [12] 12Department of Microbiology, Biochemistry, and Molecular Genetics, University Hospital Cancer Center, Rutgers Cancer Institute of New Jersey, New Jersey Medical School , Newark, NJ, USA
                [13] 13Laboratory of Molecular and Cellular Therapy, Vrije Universiteit Brussel , Jette, Belgium
                [14] 14Faculty of Life Sciences, University of Manchester , Manchester, UK
                [15] 15Department of Internal Medicine 3 – Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nurnberg , Erlangen, Germany
                [16] 16Department of Experimental Medicine, Sapienza University of Rome , Rome, Italy
                [17] 17de Duve Institute, Université Catholique de Louvain , Brussels, Belgium
                [18] 18Department of Radiation Oncology, University Hospitals Leuven, KU Leuven – University of Leuven , Leuven, Belgium
                [19] 19Department of Biological and Environmental Science and Technology, University of Salento , Salento, Italy
                [20] 20Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven – University of Leuven , Leuven, Belgium
                [21] 21Sapienza University of Rome , Rome, Italy
                [22] 22SOTIO , Prague, Czech Republic
                [23] 23Department of Immunology, 2nd Faculty of Medicine, University Hospital Motol, Charles University , Prague, Czech Republic
                [24] 24Department of Radiation Oncology, Universitätsklinikum Erlangen , Erlangen, Germany
                [25] 25Department of Immunology, Medical University of Warsaw , Warsaw, Poland
                [26] 26Biotherapy and Vaccine Unit, Institut Pasteur , Paris, France
                [27] 27Wellman Center for Photomedicine, Massachusetts General Hospital , Boston, MA, USA
                [28] 28Cancer Gene Therapy Group, Transplantation Laboratory, Haartman Institute, University of Helsinki , Helsinki, Finland
                [29] 29Helsinki University Hospital Comprehensive Cancer Center , Helsinki, Finland
                [30] 30TILT Biotherapeutics Ltd. , Helsinki, Finland
                [31] 31Recombinant Vaccine Group, Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health , Bethesda, MD, USA
                [32] 32Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute , Villejuif, France
                [33] 33Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP , Paris, France
                [34] 34Department of Women’s and Children’s Health, Karolinska University Hospital , Stockholm, Sweden
                [35] 35Molecular Signaling and Cell Death Unit, Inflammation Research Center, VIB , Ghent, Belgium
                [36] 36Department of Biomedical Molecular Biology, Ghent University , Ghent, Belgium
                [37] 37Molecular ImmunoRheumatology, INSERM UMRS1109, Laboratory of Excellence Transplantex, University of Strasbourg , Strasbourg, France
                [38] 38Institute of Molecular Biosciences, NAWI Graz, University of Graz , Graz, Austria
                [39] 39BioTechMed Graz , Graz, Austria
                [40] 40IRRCS Istituto Scientifico San Raffaele, Università Vita-Salute San Raffaele , Milan, Italy
                [41] 41Translational Research Institute, University of Queensland Diamantina Institute, University of Queensland , Wooloongabba, QLD, Australia
                [42] 42Laboratory of Cellular and Molecular Nutrition, Department of Ecological and Biological Sciences, Tuscia University , Viterbo, Italy
                [43] 43Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München , Munich, Germany
                [44] 44Department of Medical Oncology, University Hospital , Bern, Switzerland
                [45] 45INSERM, U1065, Université de Nice-Sophia-Antipolis, Centre Méditerranéen de Médecine Moléculaire (C3M), Équipe “Contrôle Métabolique des Morts Cellulaires” , Nice, France
                [46] 46Department of Oncology, University of Turin , Turin, Italy
                [47] 47Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Insitute , Herston, QLD, Australia
                [48] 48School of Medicine, University of Queensland , Herston, QLD, Australia
                [49] 49Department of Paediatric Haematology and Oncology, Children’s Clinic, Jena University Hospital , Jena, Germany
                [50] 50Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Institut du Cancer de Montréal, Faculté de Pharmacie, Université de Montréal , Montreal, QC, Canada
                [51] 51Laboratory of Pediatric Immunology, Department of Microbiology and Immunology, KU Leuven – University of Leuven , Leuven, Belgium
                [52] 52Ludwig Institute for Cancer Research, de Duve Institute, Université Catholique de Louvain , Brussels, Belgium
                [53] 53Department of Ecological and Biological Sciences, Tuscia University , Viterbo, Italy
                [54] 54University of Paris Sud , Le Kremlin-Bicêtre, France
                [55] 55U1015, INSERM , Villejuif, France
                [56] 56Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 507 , Villejuif, France
                Author notes

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

                Reviewed by: Luis De La Cruz-Merino, Hospital Universitario Virgen Macarena, Spain; Carlos Alfaro, Clínica Universidad de Navarra, Spain

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

                Article
                10.3389/fimmu.2015.00588
                4653610
                26635802
                02535cef-b37b-4870-8369-0ea7519f914a
                Copyright © 2015 Garg, Galluzzi, Apetoh, Baert, Birge, Bravo-San Pedro, Breckpot, Brough, Chaurio, Cirone, Coosemans, Coulie, De Ruysscher, Dini, de Witte, Dudek-Peric, Faggioni, Fucikova, Gaipl, Golab, Gougeon, Hamblin, Hemminki, Herrmann, Hodge, Kepp, Kroemer, Krysko, Land, Madeo, Manfredi, Mattarollo, Maueroder, Merendino, Multhoff, Pabst, Ricci, Riganti, Romano, Rufo, Smyth, Sonnemann, Spisek, Stagg, Vacchelli, Vandenabeele, Vandenberk, Van den Eynde, Van Gool, Velotti, Zitvogel and Agostinis.

                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
                : 17 September 2015
                : 02 November 2015
                Page count
                Figures: 2, Tables: 8, Equations: 0, References: 246, Pages: 24, Words: 17338
                Categories
                Immunology
                Classification

                Immunology
                anti-tumor immunity,immunogenicity,immunotherapy,molecular medicine,oncoimmunology,patient prognosis,translational medicine

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