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ANNUAL REVIEWS
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Further
Annu. Rev. Immunol. 2013.31:51-72. Downloaded from www.annualreviews.org by INSERM-multi-site account on 08/27/13. For personal use only.
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Immunogenic Cell Death in Cancer Therapy Guido Kroemer,1,3,6−9,∗ Lorenzo Galluzzi, 5,8,∗ Oliver Kepp,1,5,9 and Laurence Zitvogel2,4,9 1
U848, 2 U1015, INSERM, 94805 Villejuif, France; email:
[email protected]
3
Metabolomics Platform, 4 Center of Clinical Investigations, Institut Gustave Roussy, 94805 Villejuif, France
5
Institut Gustave Roussy, 94805 Villejuif, France
6
Equipe 11 Labellis´ee par la Ligue Nationale Contre le Cancer, Centre de Recherche des Cordeliers, 75006 Paris, France
7
Pole Europ´een Georges Pompidou, AP-HP, 75015 Paris, France ˆ de Biologie, Hopital ˆ
8
Universit´e Paris Descartes/V, Sorbonne Paris Cit´e, 75006 Paris, France
9
Universit´e Paris Sud/XI, 94805 Villejuif, France
Annu. Rev. Immunol. 2013. 31:51–72
Keywords
First published online as a Review in Advance on November 12, 2012
ATP, autophagy, calreticulin, damage-associated molecular patterns, HMGB1, TLR4
The Annual Review of Immunology is online at immunol.annualreviews.org This article’s doi: 10.1146/annurev-immunol-032712-100008 c 2013 by Annual Reviews. Copyright All rights reserved ∗
These authors contributed equally to this work.
Abstract Depending on the initiating stimulus, cancer cell death can be immunogenic or nonimmunogenic. Immunogenic cell death (ICD) involves changes in the composition of the cell surface as well as the release of soluble mediators, occurring in a defined temporal sequence. Such signals operate on a series of receptors expressed by dendritic cells to stimulate the presentation of tumor antigens to T cells. We postulate that ICD constitutes a prominent pathway for the activation of the immune system against cancer, which in turn determines the long-term success of anticancer therapies. Hence, suboptimal regimens (failing to induce ICD), selective alterations in cancer cells (preventing the emission of immunogenic signals during ICD), or defects in immune effectors (abolishing the perception of ICD by the immune system) can all contribute to therapeutic failure. We surmise that ICD and its subversion by pathogens also play major roles in antiviral immune responses.
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INTRODUCTION ICD: immunogenic cell death CTL: cytotoxic CD8+ T lymphocyte Treg: FOXP3+ regulatory T cell DC: dendritic cell
Annu. Rev. Immunol. 2013.31:51-72. Downloaded from www.annualreviews.org by INSERM-multi-site account on 08/27/13. For personal use only.
TLR: Toll-like receptor
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Every second, in the healthy human adult, several millions of cells that succumb to programmed cell death mechanisms are efficiently removed without eliciting local or systemic inflammation. This homeostatic cell death, which often occurs through apoptosis, is considered either as a tolerogenic (promoting tolerance to self) or as a null (exerting no impact on the immune system) event (1, 2). The past few years have witnessed the emergence of the concept of immunogenic cell death (ICD), i.e., a cell death modality that does stimulate an immune response against dead-cell antigens, in particular when they derive from cancer cells (2). This model was first proposed in the context of anticancer chemotherapy, based on clinical evidence indicating that tumor-specific immune responses can determine the efficacy of anticancer therapies with conventional cytotoxic drugs (3). In response to antineoplastic agents, the composition of the tumor immune infiltrate changes, and this can be crucial for the outcomes of therapy. Thus, an increased number of T lymphocytes as well as an increased ratio of cytotoxic CD8+ T lymphocytes (CTLs) over FOXP3+ regulatory T cells (Tregs) within the tumor after chemotherapy predict favorable therapeutic responses in human breast and colorectal cancer patients treated with anthracyclines and oxaliplatin, respectively (4–8). Metaanalyses of multiple clinical studies indicate that severe lymphopenia (
