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Oncoimmunology. 2014 Dec 13;3(9):e955691. eCollection 2014 Oct.

Consensus guidelines for the detection of immunogenic cell death.

Author information

1
Equipe 11 labellisée par la Ligue Nationale contre le Cancer; Center de Recherche des Cordeliers ; Paris, France ; INSERM; U1138 ; Paris, France ; Metabolomics and Cell Biology Platforms; Gustave Roussy Cancer Campus ; Villejuif, France.
2
INSERM; U1138 ; Paris, France ; Metabolomics and Cell Biology Platforms; Gustave Roussy Cancer Campus ; Villejuif, France ; INSERM; U1015 ; Villejuif, France.
3
Regina Elena National Cancer Institute ; Rome, Italy.
4
Equipe 11 labellisée par la Ligue Nationale contre le Cancer; Center de Recherche des Cordeliers ; Paris, France ; INSERM; U1138 ; Paris, France ; Gustave Roussy Cancer Campus ; Villejuif, France.
5
Equipe 11 labellisée par la Ligue Nationale contre le Cancer; Center de Recherche des Cordeliers ; Paris, France ; INSERM; U1138 ; Paris, France ; Gustave Roussy Cancer Campus ; Villejuif, France ; Molecular Cell Biology Laboratory; Department of Immunology; Institute of Biomedical Sciences; University of São Paulo ; São Paulo, Brazil.
6
Cell Death Research and Therapy (CDRT) Laboratory; Department of Cellular and Molecular Medicine; University of Leuven ; Leuven, Belgium.
7
INSERM; UMR866 ; Dijon, France ; Centre Georges François Leclerc ; Dijon, France ; Université de Bourgogne ; Dijon, France.
8
Departement of Internal Medicine and Medical Sciences; University of Rome La Sapienza ; Rome, Italy ; Istituto Pasteur; Fondazione Cenci Bolognetti ; Rome, Italy.
9
Department of Hematology; Oncology and Molecular Medicine; Istituto Superiore di Sanità (ISS) ; Rome, Italy.
10
Laboratory of Molecular and Cellular Therapy (LMCT); Department of Biomedical Sciences Medical School of the Free University of Brussels (VUB) ; Jette, Belgium.
11
Faculty of Life Sciences; University of Manchester ; Manchester, UK.
12
Department of Neurosurgery and Cell and Developmental Biology; University of Michigan School of Medicine ; Ann Arbor, MI USA.
13
Department of Experimental Medicine; University of Rome La Sapienza ; Rome, Italy.
14
Laboratorio de Biología Celular y Molecular; Instituto de Histología y Embriología (IHEM); Facultad de Ciencias Médicas; Universidad Nacional de Cuyo; CONICET ; Mendoza, Argentina.
15
INSERM; U1138 ; Paris, France ; Université Pierre et Marie Curie/Paris VI ; Paris, France ; Equipe 13; Center de Recherche des Cordeliers ; Paris, France.
16
Department of Pathology; New York University School of Medicine ; New York, NY USA.
17
Department of Biological and Environmental Science and Technology (DiSTeBA); University of Salento ; Lecce, Italy.
18
Molecular and Cellular Biology Laboratory; Division of Basic Sciences; University of Crete Medical School ; Heraklion, Greece ; Institute of Molecular Biology and Biotechnology; Foundation of Research and Technology - Hellas ; Heraklion, Greece.
19
Department of Radiation Oncology; NewYork University School of Medicine and Langone Medical Center ; New York, NY USA.
20
Department of Immunology; 2nd Faculty of Medicine and University Hospital Motol, Charles University ; Prague, Czech Republic ; Sotio ; Prague, Czech Republic.
21
Department of Radiation Oncology; University Hospital Erlangen; University of Erlangen-Nürnberg ; Erlangen, Germany.
22
INSERM; U1138 ; Paris, France ; Université Pierre et Marie Curie/Paris VI ; Paris, France ; Université Paris Descartes/Paris V; Sorbonne Paris Cité ; Paris, France ; Laboratory of Integrative Cancer Immunology; Center de Recherche des Cordeliers ; Paris, France.
23
European Pancreas Center; Department of Surgery; University Hospital Heidelberg ; Heidelberg, Germany.
24
Department of Surgery; University of Pittsburgh ; Pittsburgh, PA USA.
25
Cancer Gene Therapy Group; Transplantation laboratory; Haartman Institute; University of Helsinki ; Helsinki, Finland.
26
Department of Internal Medicine 3; University of Erlangen-Nuremberg ; Erlangen, Germany.
27
Laboratory of Tumor Immunology and Biology; Center for Cancer Research; National Cancer Institute (NCI), National Institutes of Health (NIH) ; Bethesda, MD USA.
28
Institute of Clinical Chemistry and Clinical Pharmacology; University Hospital Bonn ; Bonn, Germany.
29
Faculty of Medical and Human Sciences, Institute of Cancer Studies; Manchester Academic Health Sciences Center; University of Manchester ; Manchester, UK.
30
Cancer Research and Biotherapy Center; Second Affiliated Hospital of Southeast University ; Nanjing, China ; Laboratory of Cancer Immunobiology; Earle A. Chiles Research Institute; Providence Portland Medical Center ; Portland, OR USA.
31
Department of Surgery; National University of Singapore ; Singapore, Singapore ; Cancer Science Institute of Singapore; National University of Singapore ; Singapore, Singapore.
32
British Columbia Cancer Agency ; Vancouver, Canada.
33
VIB Inflammation Research Center ; Ghent, Belgium ; Department of Biomedical Molecular Biology; Ghent University ; Ghent, Belgium.
34
Division of Cancer Medicine and Division of Research; Peter MacCallum Cancer Center; East Melbourne ; Victoria, Australia.
35
Unit of Clinical and Experimental Immunology; Humanitas Clinical and Research Center ; Milan, Italy ; Department of Medical Biotechnologies and Translational Medicine, University of Milan ; Rozzano, Italy.
36
Institute of Molecular Biosciences; University of Graz ; Graz, Austria.
37
University Vita-Salute San Raffaele ; Milano, Italy ; San Raffaele Scientific Institute ; Milano, Italy.
38
Gustave Roussy Cancer Campus ; Villejuif, France ; INSERM, U1030 ; Villejuif, France ; Faculté de Médecine; Université Paris-Sud/Paris XI ; Kremlin-Bicêtre, France.
39
Equipe 11 labellisée par la Ligue Nationale contre le Cancer; Center de Recherche des Cordeliers ; Paris, France ; INSERM; U1138 ; Paris, France ; Gustave Roussy Cancer Campus ; Villejuif, France ; Cancer Immunology Unit, Research Department of Haematology; University College London (UCL) Cancer Institute ; London, UK.
40
Department of Ecological and Biological Sciences (DEB), Tuscia University ; Viterbo, Italy.
41
Cellular and Molecular Immunology and Endocrinology , Oniris; Nantes, France.
42
Department of Pathology and Molecular Medicine; McMaster Immunology Research Center ; Hamilton, Canada ; Institute for Infectious Disease Research; McMaster University ; Hamilton, Canada.
43
Department of Radiation Oncology; Klinikum rechts der Isar; Technical University of Munich ; Munich, Germany.
44
Comprehensive Cancer Center; Medical University of Vienna ; Vienna, Austria.
45
Department of Oncology-Pathology; Karolinska Institute ; Stockholm, Sweden.
46
INSERM; U1065 ; Nice, France ; Equipe "Contrôle Métabolique des Morts Cellulaires," Center Méditerranéen de Médecine Moléculaire (C3M) ; Nice, France ; Faculté de Médecine; Université de Nice Sophia Antipolis ; Nice, France ; Centre Hospitalier Universitaire de Nice ; Nice, France.
47
Department of Oncology and Subalpine Center for Research and Experimental Medicine (CeRMS); University of Turin ; Turin, Italy.
48
Cell Biology Unit; Azienda Ospedaliera Universitaria San Martino ; Istituto Nazionale per la Ricerca sul Cancro ; Genova, Italy.
49
Immunology in Cancer and Infection Laboratory; QIMR Berghofer Medical Research Institute ; Herston, Australia ; School of Medicine, University of Queensland ; Herston, Australia.
50
Department of Pediatric Haematology and Oncology; Jena University Hospital, Children's Clinic ; Jena, Germany.
51
Centre de Recherche du Center Hospitalier de l'Université de Montréal; Faculté de Pharmacie, Université de Montréal ; Montréal, Canada.
52
Equipe 11 labellisée par la Ligue Nationale contre le Cancer; Center de Recherche des Cordeliers ; Paris, France ; INSERM; U1138 ; Paris, France ; Gustave Roussy Cancer Campus ; Villejuif, France ; Department of Pathology, Dow International Medical College; Dow University of Health Sciences ; Karachi, Pakistan.
53
INSERM; U970 ; Paris, France ; Pôle de Biologie; Hôpital Européen Georges Pompidou; AP-HP ; Paris, France.
54
Department of Pharmacology; University of Colorado School of Medicine ; Aurora, CO USA.
55
VIB Inflammation Research Center ; Ghent, Belgium ; Department of Biomedical Molecular Biology; Ghent University ; Ghent, Belgium ; Methusalem Program; Ghent University ; Ghent, Belgium.
56
University of Hawaii Cancer Center ; Honolulu, HI USA.
57
Department of Molecular Genetics and Microbiology; Stony Brook University ; Stony Brook, NY USA.
58
INSERM; U1015 ; Villejuif, France ; Gustave Roussy Cancer Campus ; Villejuif, France ; Centre d'Investigation Clinique Biothérapie 507 (CICBT507); Gustave Roussy Cancer Campus ; Villejuif, France.
59
Equipe 11 labellisée par la Ligue Nationale contre le Cancer; Center de Recherche des Cordeliers ; Paris, France ; INSERM; U1138 ; Paris, France ; Metabolomics and Cell Biology Platforms; Gustave Roussy Cancer Campus ; Villejuif, France ; Université Paris Descartes/Paris V; Sorbonne Paris Cité ; Paris, France ; Pôle de Biologie; Hôpital Européen Georges Pompidou; AP-HP ; Paris, France.
60
Equipe 11 labellisée par la Ligue Nationale contre le Cancer; Center de Recherche des Cordeliers ; Paris, France ; INSERM; U1138 ; Paris, France ; Gustave Roussy Cancer Campus ; Villejuif, France ; Université Paris Descartes/Paris V; Sorbonne Paris Cité ; Paris, France.

Abstract

Apoptotic cells have long been considered as intrinsically tolerogenic or unable to elicit immune responses specific for dead cell-associated antigens. However, multiple stimuli can trigger a functionally peculiar type of apoptotic demise that does not go unnoticed by the adaptive arm of the immune system, which we named "immunogenic cell death" (ICD). ICD is preceded or accompanied by the emission of a series of immunostimulatory damage-associated molecular patterns (DAMPs) in a precise spatiotemporal configuration. Several anticancer agents that have been successfully employed in the clinic for decades, including various chemotherapeutics and radiotherapy, can elicit ICD. Moreover, defects in the components that underlie the capacity of the immune system to perceive cell death as immunogenic negatively influence disease outcome among cancer patients treated with ICD inducers. Thus, ICD has profound clinical and therapeutic implications. Unfortunately, the gold-standard approach to detect ICD relies on vaccination experiments involving immunocompetent murine models and syngeneic cancer cells, an approach that is incompatible with large screening campaigns. Here, we outline strategies conceived to detect surrogate markers of ICD in vitro and to screen large chemical libraries for putative ICD inducers, based on a high-content, high-throughput platform that we recently developed. Such a platform allows for the detection of multiple DAMPs, like cell surface-exposed calreticulin, extracellular ATP and high mobility group box 1 (HMGB1), and/or the processes that underlie their emission, such as endoplasmic reticulum stress, autophagy and necrotic plasma membrane permeabilization. We surmise that this technology will facilitate the development of next-generation anticancer regimens, which kill malignant cells and simultaneously convert them into a cancer-specific therapeutic vaccine.

KEYWORDS:

APC, antigen-presenting cell; ATF6, activating transcription factor 6; ATP release; BAK1, BCL2-antagonist/killer 1; BAX, BCL2-associated X protein; BCL2, B-cell CLL/lymphoma 2 protein; CALR, calreticulin; CTL, cytotoxic T lymphocyte; DAMP, damage-associated molecular pattern; DAPI, 4′,6-diamidino-2-phenylindole; DiOC6(3), 3,3′-dihexyloxacarbocyanine iodide; EIF2A, eukaryotic translation initiation factor 2A; ER, endoplasmic reticulum; FLT3LG, fms-related tyrosine kinase 3 ligand; G3BP1, GTPase activating protein (SH3 domain) binding protein 1; GFP, green fluorescent protein; H2B, histone 2B; HMGB1; HMGB1, high mobility group box 1; HSP, heat shock protein; HSV-1, herpes simplex virus type I; ICD, immunogenic cell death; IFN, interferon; IL, interleukin; MOMP, mitochondrial outer membrane permeabilization; PDIA3, protein disulfide isomerase family A; PI, propidium iodide; RFP, red fluorescent protein; TLR, Toll-like receptor; XBP1, X-box binding protein 1; autophagy; calreticulin; endoplasmic reticulum stress; immunotherapy; member 3; Δψm, mitochondrial transmembrane potential

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