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Journal of Molecular Medicine

, Volume 85, Issue 10, pp 1069–1076 | Cite as

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

  • Nathalie Chaput
  • Stéphane De Botton
  • Michel Obeid
  • Lionel Apetoh
  • François Ghiringhelli
  • Theocharis Panaretakis
  • Caroline Flament
  • Laurence Zitvogel
  • Guido Kroemer
Review

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.

Keywords

Calreticulin Chemotherapy Tumour cell Immune system Dendritic cells 

Notes

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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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Nathalie Chaput
    • 1
    • 2
  • Stéphane De Botton
    • 3
  • Michel Obeid
    • 4
    • 5
  • Lionel Apetoh
    • 2
  • François Ghiringhelli
    • 1
    • 2
  • Theocharis Panaretakis
    • 4
    • 5
  • Caroline Flament
    • 1
    • 2
  • Laurence Zitvogel
    • 1
    • 2
    • 5
  • Guido Kroemer
    • 4
    • 5
    • 6
  1. 1.Centre d’Investigation Clinique BiothérapieInstitut Gustave RoussyVillejuifFrance
  2. 2.Institut National de la Santé et de la Recherche MédicaleVillejuifFrance
  3. 3.Service d’hématologie CliniqueInstitut Gustave RoussyVillejuifFrance
  4. 4.Institut National de la Santé et de la Recherche MédicaleVillejuifFrance
  5. 5.Faculté Paris Sud-Université Paris 11Kremlin BicêtreFrance
  6. 6.INSERM, U848, Institut Gustave RoussyVillejuifFrance

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