Calreticulin exposure dictates the immunogenicity of cancer cell death

Michel Obeid; Antoine Tesniere; François Ghiringhelli; Gian Maria Fimia; Lionel Apetoh; Jean-Luc Perfettini; Maria Castedo; Grégoire Mignot; Theoharis Panaretakis; Noelia Casares; Didier Métivier; Nathanael Larochette; Peter van Endert; Fabiola Ciccosanti; Mauro Piacentini; Laurence Zitvogel; Guido Kroemer

doi:10.1038/nm1523

Calreticulin exposure dictates the immunogenicity of cancer cell death

Nat Med. 2007 Jan;13(1):54-61. doi: 10.1038/nm1523. Epub 2006 Dec 24.

Authors

Michel Obeid¹, Antoine Tesniere, François Ghiringhelli, Gian Maria Fimia, Lionel Apetoh, Jean-Luc Perfettini, Maria Castedo, Grégoire Mignot, Theoharis Panaretakis, Noelia Casares, Didier Métivier, Nathanael Larochette, Peter van Endert, Fabiola Ciccosanti, Mauro Piacentini, Laurence Zitvogel, Guido Kroemer

Affiliation

¹ INSERM U848, 39 Rue Camille-Desmoulins, F-94805 Villejuif, France.

PMID: 17187072
DOI: 10.1038/nm1523

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anthracyclines / pharmacology
Anthracyclines / therapeutic use
Antigens, Differentiation / metabolism
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use
Apoptosis / drug effects
Apoptosis / immunology*
Calreticulin / genetics
Calreticulin / immunology*
Calreticulin / metabolism
Cell Cycle Proteins / antagonists & inhibitors
Cell Cycle Proteins / metabolism
Cell Line, Tumor
Cell Membrane / drug effects
Cell Membrane / immunology
Cell Membrane / metabolism
Colonic Neoplasms / drug therapy
Colonic Neoplasms / metabolism*
Colonic Neoplasms / pathology
Dendritic Cells / immunology
Electrophoresis, Gel, Two-Dimensional
Etoposide / pharmacology
Etoposide / therapeutic use
Immunoblotting
Mice
Mice, Inbred BALB C
Mice, Nude
Mitomycin / pharmacology
Mitomycin / therapeutic use
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / immunology
Neoplasms, Experimental / metabolism
Phagocytosis / immunology
Protein Phosphatase 1
Protein Transport / drug effects
RNA Interference
Recombinant Proteins / pharmacology

Substances

Anthracyclines
Antigens, Differentiation
Antineoplastic Agents
Calreticulin
Cell Cycle Proteins
Recombinant Proteins
Mitomycin
Etoposide
Ppp1r15a protein, mouse
Protein Phosphatase 1