title: Screening of novel immunogenic cell death inducers within the NCI Mechanistic Diversity Set.
abstract: Immunogenic cell death (ICD) inducers can be defined as agents that exert cytotoxic effects while stimulating an immune response against dead cell-associated antigens. When initiated by anthracyclines, ICD is accompanied by stereotyped molecular changes, including the pre-apoptotic exposure of calreticulin (CRT) on the cell surface, the lysosomal secretion of ATP during the blebbing phase of apoptosis, and the release of high mobility group box 1 (HMGB1) from dead cells. By means of genetically engineered human osteosarcoma U2OS cells, we screened the 879 anticancer compounds of the National Cancer Institute (NCI) Mechanistic Diversity Set for their ability to promote all these hallmarks of ICD in vitro. In line with previous findings from our group, several cardiac glycosides exhibit a robust propensity to elicit the major manifestations of ICD in cultured neoplastic cells. This screen pointed to septacidin, an antibiotic produced byStreptomyces fibriatus, as a novel putative inducer of ICD. In low-throughput validation experiments, septacidin promoted CRT exposure, ATP secretion and HGMB1 release from both U2OS cells and murine fibrosarcoma MCA205 cells. Moreover, septacidin-killed MCA205 cells protected immunocompetent mice against a re-challenge with living cancer cells of the same type. Finally, the antineoplastic effects of septacidin on established murine tumors were entirely dependent on T lymphocytes. Altogether, these results underscore the suitability of the high-throughput screening system described here for the identification of novel ICD inducers.
authors: Equipe 11 labellisée par la Ligue Nationale contre le cancer, Centre de Recherche des Cordeliers; Paris, France ; INSERM, U1138; Paris, France ; Gustave Roussy Comprehensive Cancer Center; Villejuif, France.
authors: Abdul Qader
authors: AQ
authors: Sukkurwala
authors: Equipe 11 labellisée par la Ligue Nationale contre le cancer, Centre de Recherche des Cordeliers; Paris, France ; INSERM, U1138; Paris, France ; Gustave Roussy Comprehensive Cancer Center; Villejuif, France.
authors: Sandy
authors: S
authors: Adjemian
authors: Equipe 11 labellisée par la Ligue Nationale contre le cancer, Centre de Recherche des Cordeliers; Paris, France ; INSERM, U1138; Paris, France ; Gustave Roussy Comprehensive Cancer Center; Villejuif, France ; INSERM, U1015; Villejuif, France.
authors: Laura
authors: L
authors: Senovilla
authors: Equipe 11 labellisée par la Ligue Nationale contre le cancer, Centre de Recherche des Cordeliers; Paris, France ; INSERM, U1138; Paris, France ; Gustave Roussy Comprehensive Cancer Center; Villejuif, France.
authors: Mickaël
authors: M
authors: Michaud
authors: Equipe 11 labellisée par la Ligue Nationale contre le cancer, Centre de Recherche des Cordeliers; Paris, France ; INSERM, U1138; Paris, France ; Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Center; Villejuif, France.
authors: Sabrina
authors: S
authors: Spaggiari
authors: Equipe 11 labellisée par la Ligue Nationale contre le cancer, Centre de Recherche des Cordeliers; Paris, France ; INSERM, U1138; Paris, France ; Gustave Roussy Comprehensive Cancer Center; Villejuif, France.
authors: Erika
authors: E
authors: Vacchelli
authors: Equipe 11 labellisée par la Ligue Nationale contre le cancer, Centre de Recherche des Cordeliers; Paris, France ; INSERM, U1138; Paris, France ; Gustave Roussy Comprehensive Cancer Center; Villejuif, France.
authors: Elisa Elena
authors: EE
authors: Baracco
authors: Equipe 11 labellisée par la Ligue Nationale contre le cancer, Centre de Recherche des Cordeliers; Paris, France ; INSERM, U1138; Paris, France ; Gustave Roussy Comprehensive Cancer Center; Villejuif, France ; Université Paris Descartes/Paris 5; Sorbonne Paris Cité; Paris, France.
authors: Lorenzo
authors: L
authors: Galluzzi
authors: Gustave Roussy Comprehensive Cancer Center; Villejuif, France ; INSERM, U1015; Villejuif, France ; Université de Paris Saclay, Faculté de Médecine; Le Kremlin Bicêtre, France ; Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 507; Villejuif, France.
authors: Laurence
authors: L
authors: Zitvogel
authors: Equipe 11 labellisée par la Ligue Nationale contre le cancer, Centre de Recherche des Cordeliers; Paris, France ; INSERM, U1138; Paris, France ; Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Center; Villejuif, France.
authors: Oliver
authors: O
authors: Kepp
authors: Equipe 11 labellisée par la Ligue Nationale contre le cancer, Centre de Recherche des Cordeliers; Paris, France ; INSERM, U1138; Paris, France ; Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Center; Villejuif, France ; Université Paris Descartes/Paris 5; Sorbonne Paris Cité; Paris, France ; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP; Paris, France.
authors: Guido
authors: G
authors: Kroemer
keywords: C57BL/6 mice; HTS; apoptosis; autophagy; dendritic cells; mitoxantrone