Article abstract
Nature Medicine 13, 54 - 61 (2006)
Published online: 24 December 2006 | doi:10.1038/nm1523
Calreticulin exposure dictates the immunogenicity of cancer cell death
Michel Obeid1,2,3, Antoine Tesniere1,2,3, François Ghiringhelli2,3,4, Gian Maria Fimia5, Lionel Apetoh2,3,4, Jean-Luc Perfettini1,2,3, Maria Castedo1,2,3, Grégoire Mignot2,3,4, Theoharis Panaretakis1,2,3, Noelia Casares1,2,3, Didier Métivier1,2,3, Nathanael Larochette1,2,3, Peter van Endert6,7, Fabiola Ciccosanti5, Mauro Piacentini5,8, Laurence Zitvogel2,3,4,9 & Guido Kroemer1,2,3,9
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.
- INSERM U848, 39 Rue Camille-Desmoulins, F-94805 Villejuif, France.
- Institut Gustave Roussy, 39 Rue Camille-Desmoulins, F-94805 Villejuif, France.
- Faculté Paris Sud-Université Paris 11, 39 Rue Camille-Desmoulins, F-94805 Villejuif, France.
- INSERM U805, 39 Rue Camille-Desmoulins, F-94805 Villejuif, France.
- National Institute for Infectious Diseases Lazzaro Spallanzani, Via Portuense 292, I-00149 Rome, Italy.
- INSERM U580, Hopital Necker, 161 Rue de Sevres, Paris F-75015, France.
- Université Paris Descartes, 161 Rue de Sevres, Paris F-75015, France.
- Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, I-00173 Rome, Italy.
- These authors contributed equally to this work.
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