Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death.
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.
Casares
Noelia
N
Centre National de la Recherche Scientifique UMR8125, Institut Gustave Roussy, F-94805 Villejuif, France.
Pequignot
Marie O
MO
Tesniere
Antoine
A
Ghiringhelli
François
F
Roux
Stéphan
S
Chaput
Nathalie
N
Schmitt
Elise
E
Hamai
Ahmed
A
Hervas-Stubbs
Sandra
S
Obeid
Michel
M
Coutant
Frédéric
F
Métivier
Didier
D
Pichard
Evelyne
E
Aucouturier
Pierre
P
Pierron
Gérard
G
Garrido
Carmen
C
Zitvogel
Laurence
L
Kroemer
Guido
G
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
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