title: Contribution of RIP3 and MLKL to immunogenic cell death signaling in cancer chemotherapy.
abstract: Chemotherapy can reinstate anticancer immunosurveillance through inducing tumor immunogenic cell death (ICD). Here, we show that anthracyclines and oxaliplatin can trigger necroptosis in murine cancer cell lines expressing receptor-interacting serine-threonine kinase 3 (RIP3) and mixed lineage kinase domain-like (MLKL). Necroptotic cells featured biochemical hallmarks of ICD and stimulated anticancer immune responses in vivo. Chemotherapy normally killed Rip3 (-/-) and Mlkl (-/-) tumor cells and normally induced caspase-3 activation in such cells, yet was unable to reduce their growth in vivo. RIP3 or MLKL deficiency abolished the capacity of dying cancer cells to elicit an immune response. This could be attributed to reduced release of ATP and high mobility group box 1 (HMGB1) by RIP3 and MLKL-deficient cells. Measures designed to compensate for deficient ATP and HMGB1 signaling restored the chemotherapeutic response of Rip3 (-/-) and Mlkl (-/-) cancers. Altogether, these results suggest that RIP3 and MLKL can contribute to ICD signaling and tumor immunogenicity.
authors.affiliation: Equipe 11 labellisée Ligue contre le Cancer, Center de Recherche des Cordeliers, Institut National de la Santé Et de la Recherche Medicale (INSERM) U 1138, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Université Pierre et Marie Curie, Paris, France; Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Suzhou Institute of Systems Medicine, Suzhou, Jiangsu, China; Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: Heng
authors.initials: H
authors.lastname: Yang
authors.affiliation: Equipe 11 labellisée Ligue contre le Cancer, Center de Recherche des Cordeliers, Institut National de la Santé Et de la Recherche Medicale (INSERM) U 1138, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Université Pierre et Marie Curie, Paris, France; Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Suzhou Institute of Systems Medicine, Suzhou, Jiangsu, China; Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: Yuting
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Equipe 11 labellisée Ligue contre le Cancer, Center de Recherche des Cordeliers, Institut National de la Santé Et de la Recherche Medicale (INSERM) U 1138, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Université Pierre et Marie Curie, Paris, France; Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), Villejuif, France.
authors.forename: Guo
authors.initials: G
authors.lastname: Chen
authors.affiliation: Equipe 11 labellisée Ligue contre le Cancer, Center de Recherche des Cordeliers, Institut National de la Santé Et de la Recherche Medicale (INSERM) U 1138, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Université Pierre et Marie Curie, Paris, France; Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), Villejuif, France; University of Paris Sud XI, Kremlin Bicêtre, France.
authors.forename: Heng
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), Villejuif, France; INSERM, U1015, GRCC, Villejuif, France; Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 507, GRCC, Villejuif, France.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yamazaki
authors.affiliation: Cell Imaging and flow Cytometry platform (CICC), Center de Recherche des Cordeliers , Paris, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Klein
authors.affiliation: Equipe 11 labellisée Ligue contre le Cancer, Center de Recherche des Cordeliers, Institut National de la Santé Et de la Recherche Medicale (INSERM) U 1138, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Université Pierre et Marie Curie, Paris, France; Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), Villejuif, France.
authors.forename: Federico
authors.initials: F
authors.lastname: Pietrocola
authors.affiliation: Equipe 11 labellisée Ligue contre le Cancer, Center de Recherche des Cordeliers, Institut National de la Santé Et de la Recherche Medicale (INSERM) U 1138, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Université Pierre et Marie Curie, Paris, France; Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), Villejuif, France.
authors.forename: Erika
authors.initials: E
authors.lastname: Vacchelli
authors.affiliation: Unités Mixtes de Recherche (UMR) 9196, GRCC , Villejuif, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Souquere
authors.affiliation: Equipe 11 labellisée Ligue contre le Cancer, Center de Recherche des Cordeliers, Institut National de la Santé Et de la Recherche Medicale (INSERM) U 1138, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Université Pierre et Marie Curie, Paris, France; Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.
authors.forename: Allan
authors.initials: A
authors.lastname: Sauvat
authors.affiliation: Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), Villejuif, France; University of Paris Sud XI, Kremlin Bicêtre, France; INSERM, U1015, GRCC, Villejuif, France; Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 507, GRCC, Villejuif, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Zitvogel
authors.affiliation: Equipe 11 labellisée Ligue contre le Cancer, Center de Recherche des Cordeliers, Institut National de la Santé Et de la Recherche Medicale (INSERM) U 1138, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Université Pierre et Marie Curie, Paris, France; Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.
authors.forename: Oliver
authors.initials: O
authors.lastname: Kepp
authors.affiliation: Equipe 11 labellisée Ligue contre le Cancer, Center de Recherche des Cordeliers, Institut National de la Santé Et de la Recherche Medicale (INSERM) U 1138, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Université Pierre et Marie Curie, Paris, France; Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France; Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
keywords: ATP; HMGB1; Necroptosis; Tumor immunogenicity; chemotherapy; cytotoxic T cells; dendritic cells