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Published 19 December 2005. doi:10.1084/jem.20050915
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 12, 1691-1701
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ARTICLE

 Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death

Noelia Casares1, Marie O. Pequignot1, Antoine Tesniere1, François Ghiringhelli2, Stéphan Roux2, Nathalie Chaput2, Elise Schmitt3, Ahmed Hamai1, Sandra Hervas-Stubbs4, Michel Obeid1, Frédéric Coutant1, Didier Métivier1, Evelyne Pichard5, Pierre Aucouturier6, Gérard Pierron5, Carmen Garrido3, Laurence Zitvogel2, and Guido Kroemer1

1 Centre National de la Recherche Scientifique UMR8125, Institut Gustave Roussy, F-94805 Villejuif, France
2 Institut National de la Santé et de la Recherche Medicale (INSERM) Immunology Unit, Institut Gustave Roussy, F-94805 Villejuif, France
3 INSERM U-517, Faculty of Medicine and Pharmacy, 21033 Dijon, France
4 Unite de Biologie des Regulations Immunitaires, INSERM E 352, Institut Pasteur, 75724 Paris, Cedex 15, France
5 Institut André Lwoff, UPR-1983, Laboratoire Replication de l'ADN et Ultrastructure du Noyau, 94801 Villejuif, France
6 INSERM U712, Hopital Saint-Antoine, Paris, France

CORRESPONDENCE Guido Kroemer: kroemer{at}igr.fr

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.

Abbreviations used: DX, doxorubicin; DXZ, DX combined with Z-VAD-fmk; F/T, frozen-thawed; MC, mitomycin C; TSA, murine mammary adenocarcinoma TS/A; TUNEL, terminal desoxyribonucleotidyl transferase dUTP nick end labeling.

N. Casares and M.O. Pequignot contributed equally to this work.


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