title: The oncolytic peptide LTX-315 triggers immunogenic cell death.
abstract: LTX-315 is a cationic amphilytic peptide that preferentially permeabilizes mitochondrial membranes, thereby causing partially BAX/BAK1-regulated, caspase-independent necrosis. Based on the observation that intratumorally injected LTX-315 stimulates a strong T lymphocyte-mediated anticancer immune response, we investigated whether LTX-315 may elicit the hallmarks of immunogenic cell death (ICD), namely (i) exposure of calreticulin on the plasma membrane surface, (ii) release of ATP into the extracellular space, (iii) exodus of HMGB1 from the nucleus, and (iv) induction of a type-1 interferon response. Using a panel of biosensor cell lines and robotized fluorescence microscopy coupled to automatic image analysis, we observed that LTX-315 induces all known ICD characteristics. This conclusion was validated by several independent methods including immunofluorescence stainings (for calreticulin), bioluminescence assays (for ATP), immunoassays (for HMGB1), and RT-PCRs (for type-1 interferon induction). When injected into established cancers, LTX-315 caused a transiently hemorrhagic focal necrosis that was accompanied by massive release of HMGB1 (from close-to-all cancer cells), as well as caspase-3 activation in a fraction of the cells. LTX-315 was at least as efficient as the positive control, the anthracycline mitoxantrone (MTX), in inducing local inflammation with infiltration by myeloid cells and T lymphocytes. Collectively, these results support the idea that LTX-315 can induce ICD, hence explaining its capacity to mediate immune-dependent therapeutic effects.
authors.affiliation: Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.|Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, 15 rue de l'Ecole de Médecine, Paris, France.|Sorbonne Paris Cité, Université Paris Descartes, 15 rue de l'Ecole de Médecine, Paris, France.|University of Paris Sud XI, Kremlin Bicêtre, France.|Université Pierre et Marie Curie, 15 rue de l'Ecole de Médecine, Paris, France.
authors.forename: H
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.|Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, 15 rue de l'Ecole de Médecine, Paris, France.|Sorbonne Paris Cité, Université Paris Descartes, 15 rue de l'Ecole de Médecine, Paris, France.|University of Paris Sud XI, Kremlin Bicêtre, France.
authors.forename: S
authors.initials: S
authors.lastname: Forveille
authors.affiliation: Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.|Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, 15 rue de l'Ecole de Médecine, Paris, France.|Sorbonne Paris Cité, Université Paris Descartes, 15 rue de l'Ecole de Médecine, Paris, France.|University of Paris Sud XI, Kremlin Bicêtre, France.|Université Pierre et Marie Curie, 15 rue de l'Ecole de Médecine, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Sauvat
authors.affiliation: Sorbonne Paris Cité, Université Paris Descartes, 15 rue de l'Ecole de Médecine, Paris, France.|Department of Immuno-Oncology, Institut de Cancérologie, Gustave Roussy Cancer Campus, 114 rue Edouard Vaillant, Villejuif, France.|Institut National de la Santé et de la Recherche Medicale (INSERM), U1015, Villejuif, France.|Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 507, Villejuif, France.|Gustave Roussy Comprehensive Cancer Center, Villejuif, France.|CNRS, UMR8122, Villejuif, France.
authors.forename: T
authors.initials: T
authors.lastname: Yamazaki
authors.affiliation: Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.|Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, 15 rue de l'Ecole de Médecine, Paris, France.|Sorbonne Paris Cité, Université Paris Descartes, 15 rue de l'Ecole de Médecine, Paris, France.|University of Paris Sud XI, Kremlin Bicêtre, France.|Université Pierre et Marie Curie, 15 rue de l'Ecole de Médecine, Paris, France.
authors.forename: L
authors.initials: L
authors.lastname: Senovilla
authors.affiliation: Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.|Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, 15 rue de l'Ecole de Médecine, Paris, France.|Sorbonne Paris Cité, Université Paris Descartes, 15 rue de l'Ecole de Médecine, Paris, France.|University of Paris Sud XI, Kremlin Bicêtre, France.|Université Pierre et Marie Curie, 15 rue de l'Ecole de Médecine, Paris, France.|Suzhou Institute of Systems Medicine, Suzhou, Jiangsu, China.|Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.|Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, 15 rue de l'Ecole de Médecine, Paris, France.|Sorbonne Paris Cité, Université Paris Descartes, 15 rue de l'Ecole de Médecine, Paris, France.|University of Paris Sud XI, Kremlin Bicêtre, France.|Université Pierre et Marie Curie, 15 rue de l'Ecole de Médecine, Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Liu
authors.affiliation: Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.|Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, 15 rue de l'Ecole de Médecine, Paris, France.|Sorbonne Paris Cité, Université Paris Descartes, 15 rue de l'Ecole de Médecine, Paris, France.|University of Paris Sud XI, Kremlin Bicêtre, France.|Université Pierre et Marie Curie, 15 rue de l'Ecole de Médecine, Paris, France.|Suzhou Institute of Systems Medicine, Suzhou, Jiangsu, China.|Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
authors.forename: H
authors.initials: H
authors.lastname: Yang
authors.affiliation: Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.|Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, 15 rue de l'Ecole de Médecine, Paris, France.|Sorbonne Paris Cité, Université Paris Descartes, 15 rue de l'Ecole de Médecine, Paris, France.|University of Paris Sud XI, Kremlin Bicêtre, France.|Université Pierre et Marie Curie, 15 rue de l'Ecole de Médecine, Paris, France.
authors.forename: L
authors.initials: L
authors.lastname: Bezu
authors.affiliation: Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.|Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, 15 rue de l'Ecole de Médecine, Paris, France.|Sorbonne Paris Cité, Université Paris Descartes, 15 rue de l'Ecole de Médecine, Paris, France.|University of Paris Sud XI, Kremlin Bicêtre, France.|Université Pierre et Marie Curie, 15 rue de l'Ecole de Médecine, Paris, France.
authors.forename: K
authors.initials: K
authors.lastname: Müller
authors.affiliation: Université Pierre et Marie Curie, 15 rue de l'Ecole de Médecine, Paris, France.|Department of Immuno-Oncology, Institut de Cancérologie, Gustave Roussy Cancer Campus, 114 rue Edouard Vaillant, Villejuif, France.|Institut National de la Santé et de la Recherche Medicale (INSERM), U1015, Villejuif, France.|Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 507, Villejuif, France.|Gustave Roussy Comprehensive Cancer Center, Villejuif, France.|CNRS, UMR8122, Villejuif, France.
authors.forename: L
authors.initials: L
authors.lastname: Zitvogel
authors.affiliation: Lytix Biopharma AS, Gaustadalléen 21, Oslo, Norway.|Institute of Medical Biology, University of Tromsø, Tromsø, Norway.
authors.forename: Ø
authors.initials: Ø
authors.lastname: Rekdal
authors.affiliation: Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.|Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, 15 rue de l'Ecole de Médecine, Paris, France.|Sorbonne Paris Cité, Université Paris Descartes, 15 rue de l'Ecole de Médecine, Paris, France.|University of Paris Sud XI, Kremlin Bicêtre, France.|Gustave Roussy Comprehensive Cancer Center, Villejuif, France.|CNRS, UMR8122, Villejuif, France.
authors.forename: O
authors.initials: O
authors.lastname: Kepp
authors.affiliation: Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.|Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, 15 rue de l'Ecole de Médecine, Paris, France.|Sorbonne Paris Cité, Université Paris Descartes, 15 rue de l'Ecole de Médecine, Paris, France.|University of Paris Sud XI, Kremlin Bicêtre, France.|Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.|Department of Women's and Children's Health, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: G
authors.initials: G
authors.lastname: Kroemer
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D016923:Cell Death; D045744:Cell Line, Tumor; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects*; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D009842:Oligopeptides / Q000493:pharmacokinetics*; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000276:immunology*; D051028:bcl-2-Associated X Protein / Q000276:immunology*
chemical_list: D000970:Antineoplastic Agents; C494772:BAK1 protein, human; C494826:BAX protein, human; C000609766:LTX-315; D009842:Oligopeptides; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein