title: Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death.
abstract: Systemic anticancer chemotherapy is immunosuppressive and mostly induces nonimmunogenic tumor cell death. Here, we show that even in the absence of any adjuvant, tumor cells dying in response to anthracyclins can elicit an effective antitumor immune response that suppresses the growth of inoculated tumors or leads to the regression of established neoplasia. Although both antracyclins and mitomycin C induced apoptosis with caspase activation, only anthracyclin-induced immunogenic cell death was immunogenic. Caspase inhibition by Z-VAD-fmk or transfection with the baculovirus inhibitor p35 did not inhibit doxorubicin (DX)-induced cell death, yet suppressed the immunogenicity of dying tumor cells in several rodent models of neoplasia. Depletion of dendritic cells (DCs) or CD8+T cells abolished the immune response against DX-treated apoptotic tumor cells in vivo. Caspase inhibition suppressed the capacity of DX-killed cells to be phagocytosed by DCs, yet had no effect on their capacity to elicit DC maturation. Freshly excised tumors became immunogenic upon DX treatment in vitro, and intratumoral inoculation of DX could trigger the regression of established tumors in immunocompetent mice. These results delineate a procedure for the generation of cancer vaccines and the stimulation of anti-neoplastic immune responses in vivo.
authors.affiliation: Centre National de la Recherche Scientifique UMR8125, Institut Gustave Roussy, F-94805 Villejuif, France.
authors.forename: Noelia
authors.initials: N
authors.lastname: Casares
authors.forename: Marie O
authors.initials: MO
authors.lastname: Pequignot
authors.forename: Antoine
authors.initials: A
authors.lastname: Tesniere
authors.forename: François
authors.initials: F
authors.lastname: Ghiringhelli
authors.forename: Stéphan
authors.initials: S
authors.lastname: Roux
authors.forename: Nathalie
authors.initials: N
authors.lastname: Chaput
authors.forename: Elise
authors.initials: E
authors.lastname: Schmitt
authors.forename: Ahmed
authors.initials: A
authors.lastname: Hamai
authors.forename: Sandra
authors.initials: S
authors.lastname: Hervas-Stubbs
authors.forename: Michel
authors.initials: M
authors.lastname: Obeid
authors.forename: Frédéric
authors.initials: F
authors.lastname: Coutant
authors.forename: Didier
authors.initials: D
authors.lastname: Métivier
authors.forename: Evelyne
authors.initials: E
authors.lastname: Pichard
authors.forename: Pierre
authors.initials: P
authors.lastname: Aucouturier
authors.forename: Gérard
authors.initials: G
authors.lastname: Pierron
authors.forename: Carmen
authors.initials: C
authors.lastname: Garrido
authors.forename: Laurence
authors.initials: L
authors.lastname: Zitvogel
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology; D004317:Doxorubicin / Q000494:pharmacology* / Q000627:therapeutic use; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D051379:Mice; D016685:Mitomycin / Q000494:pharmacology* / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000517:prevention & control; D051381:Rats; D014611:Vaccination / Q000379:methods; D014764:Viral Proteins / Q000235:genetics / Q000494:pharmacology
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D000903:Antibiotics, Antineoplastic; D061945:Caspase Inhibitors; D014764:Viral Proteins; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C492234:p35 protein, Baculovirus; D016685:Mitomycin; D004317:Doxorubicin; D020169:Caspases