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Molecular determinants of immunogenic cell death: surface exposure of calreticulin makes the difference

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Abstract

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.

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Acknowledgment

This work was supported by a special grant from Ligue Nationale contre le Cancer (“équipes labellisées” of GK and LZ), as well as by grants from Institut National contre le Cancer (INCa), MDS Foundation, Association Laurette Fugain, Fondation de France, and European Community (RIGHT; to GK).

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Authors and Affiliations

  1. Centre d’Investigation Clinique Biothérapie, Institut Gustave Roussy, Villejuif, France

    Nathalie Chaput, François Ghiringhelli, Caroline Flament & Laurence Zitvogel

  2. Institut National de la Santé et de la Recherche Médicale, U805, 94805, Villejuif, France

    Nathalie Chaput, Lionel Apetoh, François Ghiringhelli, Caroline Flament & Laurence Zitvogel

  3. Service d’hématologie Clinique, Institut Gustave Roussy, Villejuif, France

    Stéphane De Botton

  4. Institut National de la Santé et de la Recherche Médicale, U848, 94805, Villejuif, France

    Michel Obeid, Theocharis Panaretakis & Guido Kroemer

  5. Faculté Paris Sud-Université Paris 11, Kremlin Bicêtre, France

    Michel Obeid, Theocharis Panaretakis, Laurence Zitvogel & Guido Kroemer

  6. INSERM, U848, Institut Gustave Roussy, PR1, 38 rue Camille Desmoulins, 94805, Villejuif, France

    Guido Kroemer

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  1. Nathalie Chaput
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  2. Stéphane De Botton
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Chaput, N., De Botton, S., Obeid, M. et al. Molecular determinants of immunogenic cell death: surface exposure of calreticulin makes the difference. J Mol Med 85, 1069–1076 (2007). https://doi.org/10.1007/s00109-007-0214-1

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