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      Molecular and Translational Classifications of DAMPs in Immunogenic Cell Death


      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.


          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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          Most cited references 187

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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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              Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte.

              Apoptotic-cell removal is critical for development, tissue homeostasis, and resolution of inflammation. Although many candidate systems exist, only phosphatidylserine has been identified as a general recognition ligand on apoptotic cells. We demonstrate here that calreticulin acts as a second general recognition ligand by binding and activating LDL-receptor-related protein (LRP) on the engulfing cell. Since surface calreticulin is also found on viable cells, a mechanism preventing inadvertent uptake was sought. Disruption of interactions between CD47 (integrin-associated protein) on the target cell and SIRPalpha (SHPS-1), a heavily glycosylated transmembrane protein on the engulfing cell, permitted uptake of viable cells in a calreticulin/LRP-dependent manner. On apoptotic cells, CD47 was altered and/or lost and no longer activated SIRPalpha. These changes on the apoptotic cell create an environment where "don't eat me" signals are rendered inactive and "eat me" signals, including calreticulin and phosphatidylserine, congregate together and signal for removal.

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                URI : http://frontiersin.org/people/u/125087
                URI : http://frontiersin.org/people/u/22973
                URI : http://frontiersin.org/people/u/293032
                URI : http://frontiersin.org/people/u/172499
                URI : http://frontiersin.org/people/u/48069
                URI : http://frontiersin.org/people/u/29817
                URI : http://frontiersin.org/people/u/37401
                URI : http://frontiersin.org/people/u/291730
                URI : http://frontiersin.org/people/u/212023
                URI : http://frontiersin.org/people/u/30408
                URI : http://frontiersin.org/people/u/291377
                URI : http://frontiersin.org/people/u/288672
                URI : http://frontiersin.org/people/u/32052
                URI : http://frontiersin.org/people/u/187468
                URI : http://frontiersin.org/people/u/288691
                URI : http://frontiersin.org/people/u/120137
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                20 November 2015
                : 6
                1Cell Death Research and Therapy Laboratory, Department of Cellular Molecular Medicine, KU Leuven – University of Leuven , Leuven, Belgium
                2Equipe 11 Labellisée Ligue Contre le Cancer, Centre de Recherche des Cordeliers , Paris, France
                3U1138, INSERM , Paris, France
                4Université Paris Descartes, Sorbonne Paris Cité , Paris, France
                5Université Pierre et Marie Curie , Paris, France
                6Gustave Roussy Comprehensive Cancer Institute , Villejuif, France
                7U866, INSERM , Dijon, France
                8Faculté de Médecine, Université de Bourgogne , Dijon, France
                9Centre Georges François Leclerc , Dijon, France
                10Department of Gynaecology and Obstetrics, UZ Leuven , Leuven, Belgium
                11Laboratory of Gynaecologic Oncology, Department of Oncology, Leuven Cancer Institute, KU Leuven , Leuven, Belgium
                12Department of Microbiology, Biochemistry, and Molecular Genetics, University Hospital Cancer Center, Rutgers Cancer Institute of New Jersey, New Jersey Medical School , Newark, NJ, USA
                13Laboratory of Molecular and Cellular Therapy, Vrije Universiteit Brussel , Jette, Belgium
                14Faculty of Life Sciences, University of Manchester , Manchester, UK
                15Department of Internal Medicine 3 – Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nurnberg , Erlangen, Germany
                16Department of Experimental Medicine, Sapienza University of Rome , Rome, Italy
                17de Duve Institute, Université Catholique de Louvain , Brussels, Belgium
                18Department of Radiation Oncology, University Hospitals Leuven, KU Leuven – University of Leuven , Leuven, Belgium
                19Department of Biological and Environmental Science and Technology, University of Salento , Salento, Italy
                20Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven – University of Leuven , Leuven, Belgium
                21Sapienza University of Rome , Rome, Italy
                22SOTIO , Prague, Czech Republic
                23Department of Immunology, 2nd Faculty of Medicine, University Hospital Motol, Charles University , Prague, Czech Republic
                24Department of Radiation Oncology, Universitätsklinikum Erlangen , Erlangen, Germany
                25Department of Immunology, Medical University of Warsaw , Warsaw, Poland
                26Biotherapy and Vaccine Unit, Institut Pasteur , Paris, France
                27Wellman Center for Photomedicine, Massachusetts General Hospital , Boston, MA, USA
                28Cancer Gene Therapy Group, Transplantation Laboratory, Haartman Institute, University of Helsinki , Helsinki, Finland
                29Helsinki University Hospital Comprehensive Cancer Center , Helsinki, Finland
                30TILT Biotherapeutics Ltd. , Helsinki, Finland
                31Recombinant Vaccine Group, Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health , Bethesda, MD, USA
                32Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute , Villejuif, France
                33Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP , Paris, France
                34Department of Women’s and Children’s Health, Karolinska University Hospital , Stockholm, Sweden
                35Molecular Signaling and Cell Death Unit, Inflammation Research Center, VIB , Ghent, Belgium
                36Department of Biomedical Molecular Biology, Ghent University , Ghent, Belgium
                37Molecular ImmunoRheumatology, INSERM UMRS1109, Laboratory of Excellence Transplantex, University of Strasbourg , Strasbourg, France
                38Institute of Molecular Biosciences, NAWI Graz, University of Graz , Graz, Austria
                39BioTechMed Graz , Graz, Austria
                40IRRCS Istituto Scientifico San Raffaele, Università Vita-Salute San Raffaele , Milan, Italy
                41Translational Research Institute, University of Queensland Diamantina Institute, University of Queensland , Wooloongabba, QLD, Australia
                42Laboratory of Cellular and Molecular Nutrition, Department of Ecological and Biological Sciences, Tuscia University , Viterbo, Italy
                43Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München , Munich, Germany
                44Department of Medical Oncology, University Hospital , Bern, Switzerland
                45INSERM, U1065, Université de Nice-Sophia-Antipolis, Centre Méditerranéen de Médecine Moléculaire (C3M), Équipe “Contrôle Métabolique des Morts Cellulaires” , Nice, France
                46Department of Oncology, University of Turin , Turin, Italy
                47Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Insitute , Herston, QLD, Australia
                48School of Medicine, University of Queensland , Herston, QLD, Australia
                49Department of Paediatric Haematology and Oncology, Children’s Clinic, Jena University Hospital , Jena, Germany
                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
                51Laboratory of Pediatric Immunology, Department of Microbiology and Immunology, KU Leuven – University of Leuven , Leuven, Belgium
                52Ludwig Institute for Cancer Research, de Duve Institute, Université Catholique de Louvain , Brussels, Belgium
                53Department of Ecological and Biological Sciences, Tuscia University , Viterbo, Italy
                54University of Paris Sud , Le Kremlin-Bicêtre, France
                55U1015, INSERM , Villejuif, France
                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

                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.

                Page count
                Figures: 2, Tables: 8, Equations: 0, References: 246, Pages: 24, Words: 17338


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