Calreticulin exposure dictates the immunogenicity of cancer cell death |
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Authors: | Obeid Michel Tesniere Antoine Ghiringhelli François Fimia Gian Maria Apetoh Lionel Perfettini Jean-Luc Castedo Maria Mignot Grégoire Panaretakis Theoharis Casares Noelia Métivier Didier Larochette Nathanael van Endert Peter Ciccosanti Fabiola Piacentini Mauro Zitvogel Laurence Kroemer Guido |
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Affiliation: | INSERM U848, 39 Rue Camille-Desmoulins, F-94805 Villejuif, France. |
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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. |
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