title: Calreticulin exposure dictates the immunogenicity of cancer cell death.
abstract: Anthracyclin-treated tumor cells are particularly effective in eliciting an anticancer immune response, whereas other DNA-damaging agents such as etoposide and mitomycin C do not induce immunogenic cell death. Here we show that anthracyclins induce the rapid, preapoptotic translocation of calreticulin (CRT) to the cell surface. Blockade or knockdown of CRT suppressed the phagocytosis of anthracyclin-treated tumor cells by dendritic cells and abolished their immunogenicity in mice. The anthracyclin-induced CRT translocation was mimicked by inhibition of the protein phosphatase 1/GADD34 complex. Administration of recombinant CRT or inhibitors of protein phosphatase 1/GADD34 restored the immunogenicity of cell death elicited by etoposide and mitomycin C, and enhanced their antitumor effects in vivo. These data identify CRT as a key feature determining anticancer immune responses and delineate a possible strategy for immunogenic chemotherapy.
authors.affiliation: INSERM U848, 39 Rue Camille-Desmoulins, F-94805 Villejuif, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Obeid
authors.forename: Antoine
authors.initials: A
authors.lastname: Tesniere
authors.forename: François
authors.initials: F
authors.lastname: Ghiringhelli
authors.forename: Gian Maria
authors.initials: GM
authors.lastname: Fimia
authors.forename: Lionel
authors.initials: L
authors.lastname: Apetoh
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Perfettini
authors.forename: Maria
authors.initials: M
authors.lastname: Castedo
authors.forename: Grégoire
authors.initials: G
authors.lastname: Mignot
authors.forename: Theoharis
authors.initials: T
authors.lastname: Panaretakis
authors.forename: Noelia
authors.initials: N
authors.lastname: Casares
authors.forename: Didier
authors.initials: D
authors.lastname: Métivier
authors.forename: Nathanael
authors.initials: N
authors.lastname: Larochette
authors.forename: Peter
authors.initials: P
authors.lastname: van Endert
authors.forename: Fabiola
authors.initials: F
authors.lastname: Ciccosanti
authors.forename: Mauro
authors.initials: M
authors.lastname: Piacentini
authors.forename: Laurence
authors.initials: L
authors.lastname: Zitvogel
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
mesh_terms: D000818:Animals; D018943:Anthracyclines / Q000494:pharmacology / Q000627:therapeutic use; D000943:Antigens, Differentiation / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D037282:Calreticulin / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology; D015180:Electrophoresis, Gel, Two-Dimensional; D005047:Etoposide / Q000494:pharmacology / Q000627:therapeutic use; D015151:Immunoblotting; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016685:Mitomycin / Q000494:pharmacology / Q000627:therapeutic use; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D010587:Phagocytosis / Q000276:immunology; D054645:Protein Phosphatase 1; D021381:Protein Transport / Q000187:drug effects; D034622:RNA Interference; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: D018943:Anthracyclines; D000943:Antigens, Differentiation; D000970:Antineoplastic Agents; D037282:Calreticulin; D018797:Cell Cycle Proteins; D011994:Recombinant Proteins; D016685:Mitomycin; D005047:Etoposide; C513256:Ppp1r15a protein, mouse; D054645:Protein Phosphatase 1