Calreticulin exposure dictates the immunogenicity of cancer cell death.

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.

• Authors: 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
• Journal: Nature medicine (Nat Med) Vol. 13 Issue 1 Pg. 54-61 (Jan 2007) ISSN: 1078-8956 [Print] United States
• PMID: 17187072 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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