Immunogenic tumor cell death for optimal anticancer therapy: the calreticulin exposure pathway.

Abstract

In response to some chemotherapeutic agents such as anthracyclines and oxaliplatin, cancer cells undergo immunogenic apoptosis, meaning that their corpses are engulfed by dendritic cells and that tumor cell antigens are presented to tumor-specific CD8(+) T cells, which then control residual tumor cells. One of the peculiarities of immunogenic apoptosis is the early cell surface exposure of calreticulin (CRT), a protein that usually resides in the lumen of the endoplasmic reticulum (ER). When elicited by anthracyclines or oxaliplatin, the CRT exposure pathway is activated by pre-apoptotic ER stress and the phosphorylation of the eukaryotic translation initiation factor eIF2alpha by the kinase PERK, followed by caspase-8-mediated proteolysis of the ER-sessile protein BAP31, activation of the pro-apoptotic proteins Bax and Bak, anterograde transport of CRT from the ER to the Golgi apparatus and exocytosis of CRT-containing vesicles, finally resulting in CRT translocation onto the plasma membrane surface. Interruption of this complex pathway abolishes CRT exposure, annihilates the immunogenicity of apoptosis, and reduces the immune response elicited by anticancer chemotherapies. We speculate that human cancers that are incapable of activating the CRT exposure pathway are refractory to the immune-mediated component of anticancer therapies.

• Authors: Laurence Zitvogel, Oliver Kepp, Laura Senovilla, Laurie Menger, Nathalie Chaput, Guido Kroemer
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 16 Issue 12 Pg. 3100-4 (Jun 15 2010) ISSN: 1557-3265 [Electronic] United States
• PMID: 20421432 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: (c) 2010 AACR.

Chemical References

• Anthracyclines
• Antineoplastic Agents
• Calreticulin
• Organoplatinum Compounds
• Oxaliplatin

Topics

• Animals
• Anthracyclines (therapeutic use)
• Antineoplastic Agents (therapeutic use)
• Apoptosis (immunology)
• Calreticulin (physiology)
• Cell Death (immunology)
• Cell Line, Tumor
• Dendritic Cells (immunology)
• Endoplasmic Reticulum (metabolism)
• Humans
• Neoplasm Transplantation (immunology)
• Neoplasms (immunology)
• Organoplatinum Compounds (therapeutic use)
• Oxaliplatin