Calreticulin exposure dictates the immunogenicity of cancer cell death.
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.
Obeid
Michel
M
INSERM U848, 39 Rue Camille-Desmoulins, F-94805 Villejuif, France.
Tesniere
Antoine
A
Ghiringhelli
François
F
Fimia
Gian Maria
GM
Apetoh
Lionel
L
Perfettini
Jean-Luc
JL
Castedo
Maria
M
Mignot
Grégoire
G
Panaretakis
Theoharis
T
Casares
Noelia
N
Métivier
Didier
D
Larochette
Nathanael
N
van Endert
Peter
P
Ciccosanti
Fabiola
F
Piacentini
Mauro
M
Zitvogel
Laurence
L
Kroemer
Guido
G
D000818:Animals; D018943:Anthracyclines / Q000494:pharmacology / Q000627:therapeutic use; D000943:Antigens, Differentiation / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D037282:Calreticulin / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology; D015180:Electrophoresis, Gel, Two-Dimensional; D005047:Etoposide / Q000494:pharmacology / Q000627:therapeutic use; D015151:Immunoblotting; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016685:Mitomycin / Q000494:pharmacology / Q000627:therapeutic use; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D010587:Phagocytosis / Q000276:immunology; D054645:Protein Phosphatase 1; D021381:Protein Transport / Q000187:drug effects; D034622:RNA Interference; D011994:Recombinant Proteins / Q000494:pharmacology
D018943:Anthracyclines; D000943:Antigens, Differentiation; D000970:Antineoplastic Agents; D037282:Calreticulin; D018797:Cell Cycle Proteins; D011994:Recombinant Proteins; D016685:Mitomycin; D005047:Etoposide; C513256:Ppp1r15a protein, mouse; D054645:Protein Phosphatase 1