Molecular determinants of immunogenic cell death: surface exposure of calreticulin makes the difference.
The treatment of cancer by chemotherapy causes tumour cell death, mostly by apoptosis. This tumour cell death may or may not elicit an immune response. At least in some cases, the efficacy of chemotherapy critically depends on the induction of immunogenic cell death that is a type of cell demise that stimulates the activation of an adaptative anti-tumour immune response, which in turn helps to eradicate residual cancer (stem) cells. Indeed, anthracyclins care more efficient in curing tumours in immunocompetent than in T cell-deficient mice. The molecular mechanism implicated in this anti-tumour T cell activation was recently discovered. Anthracyclins cause immunogenic cell death due to their specific capacity to stimulate the translocation of calreticulin to the cell surface. Calreticulin then acts as an "eat me" signal for dendritic cells, allowing them to phagocytose tumour cells and to prime tumour antigen-specific cytotoxic T cells. Importantly, non-immunogenic chemotherapy can be rendered immunogenic by adsorbing recombinant calreticulin to tumour cells or by enforcing the translocation of endogenous calreticulin to the cell surface by means of PP1/GADD34 inhibitors. This strategy could have major implications for the treatment of human cancer. Indeed, in vivo treatments with anthracyclins can cause the translocation of calreticulin to the surface of circulating tumour cells, in patients with acute myeloid leukaemia (AML). The challenge will be to determine whether the exposure of calreticulin translocation on the tumour cell surface is linked to chemotherapy-induced anti-tumour immune responses and therapeutic efficacy in human cancer.
Chaput
Nathalie
N
Centre d'Investigation Clinique Biothérapie, Institut Gustave Roussy, Villejuif, France.
De Botton
Stéphane
S
Obeid
Michel
M
Apetoh
Lionel
L
Ghiringhelli
François
F
Panaretakis
Theocharis
T
Flament
Caroline
C
Zitvogel
Laurence
L
Kroemer
Guido
G
D000818:Animals; D018943:Anthracyclines / Q000494:pharmacology / Q000627:therapeutic use; D000951:Antigens, Neoplasm / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D000954:Antigens, Surface / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D037282:Calreticulin / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009374:Neoplasms, Experimental / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D018943:Anthracyclines; D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D000970:Antineoplastic Agents; D037282:Calreticulin