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: Noelia Casares, Marie O Pequignot, Antoine Tesniere, François Ghiringhelli, Stéphan Roux, Nathalie Chaput, Elise Schmitt, Ahmed Hamai, Sandra Hervas-Stubbs, Michel Obeid, Frédéric Coutant, Didier Métivier, Evelyne Pichard, Pierre Aucouturier, Gérard Pierron, Carmen Garrido, Laurence Zitvogel, Guido Kroemer
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 202 Issue 12 Pg. 1691-701 (Dec 19 2005) ISSN: 0022-1007 [Print] United States
• PMID: 16365148 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acid Chloromethyl Ketones
• Antibiotics, Antineoplastic
• Caspase Inhibitors
• Viral Proteins
• benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
• p35 protein, Baculovirus
• Mitomycin
• Doxorubicin
• Caspases

Topics

• Amino Acid Chloromethyl Ketones (pharmacology)
• Animals
• Antibiotics, Antineoplastic (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• CD8-Positive T-Lymphocytes (immunology)
• Caspase Inhibitors
• Caspases (metabolism)
• Cell Line, Tumor
• Dendritic Cells (immunology)
• Doxorubicin (pharmacology, therapeutic use)
• Immunoblotting
• In Situ Nick-End Labeling
• Mice
• Mitomycin (pharmacology, therapeutic use)
• Neoplasms (drug therapy, immunology, prevention & control)
• Rats
• Vaccination (methods)
• Viral Proteins (genetics, pharmacology)