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Immunogenic cell death in cancer and infectious disease

Nature Reviews Immunology volume 17, pages 97–111 (2017)Cite this article

Subjects

Key Points

  • The immunogenicity of cell death is determined by its antigenicity and its adjuvanticity.

  • Cells infected by pathogens as well as cancer cells exhibit accrued antigenicity.

  • Stress responses in dying cells cause the emission of adjuvant-like danger signals.

  • Different sets of danger signals are associated with distinct variants of immunogenic cell death.

  • Both pathogens and cancer cells interrupt danger signalling for their own benefit.

  • Reinstating the immunogenicity of cell death holds promise for anticancer therapy.

Abstract

Immunogenicity depends on two key factors: antigenicity and adjuvanticity. The presence of exogenous or mutated antigens explains why infected cells and malignant cells can initiate an adaptive immune response provided that the cells also emit adjuvant signals as a consequence of cellular stress and death. Several infectious pathogens have devised strategies to control cell death and limit the emission of danger signals from dying cells, thereby avoiding immune recognition. Similarly, cancer cells often escape immunosurveillance owing to defects in the molecular machinery that underlies the release of endogenous adjuvants. Here, we review current knowledge on the mechanisms that underlie the activation of immune responses against dying cells and their pathophysiological relevance.

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Figure 1: Differential requirements for the immunogenicity of cell death.
Figure 2: Mechanisms of chemotherapy-driven ICD.
Figure 3: Subversion of danger signalling.

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Acknowledgements

The authors are supported by the French Ligue contre le Cancer (équipe labellisée); Agence National de la Recherche (ANR) – Projets blancs; ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases; Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; Institut National du Cancer (INCa); Institut Universitaire de France; Fondation pour la Recherche Médicale (FRM); the European Commission (ArtForce); the European Research Council (ERC); the LeDucq Foundation; the LabEx Immuno-Oncology; the SIRIC Stratified Oncology Cell DNA Repair and Tumour Immune Elimination (SOCRATE); the SIRIC Cancer Research and Personalized Medicine (CARPEM); and the Paris Alliance of Cancer Research Institutes (PACRI).

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Authors and Affiliations

  1. Department of Radiation Oncology, Weill Cornell Medical College, New York, 10065, New York, USA

    Lorenzo Galluzzi

  2. Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, 75006, Paris, France

    Lorenzo Galluzzi, Aitziber Buqué, Oliver Kepp & Guido Kroemer

  3. INSERM, U1138, 75006, Paris, France

    Lorenzo Galluzzi, Aitziber Buqué, Oliver Kepp & Guido Kroemer

  4. Université Paris Descartes/Paris V, Sorbonne Paris Cité, 75006, Paris, France

    Lorenzo Galluzzi, Aitziber Buqué, Oliver Kepp & Guido Kroemer

  5. Université Pierre et Marie Curie/Paris VI, 75006, Paris, France

    Lorenzo Galluzzi, Aitziber Buqué, Oliver Kepp & Guido Kroemer

  6. Gustave Roussy Comprehensive Cancer Institute, 94805, Villejuif, France

    Lorenzo Galluzzi, Aitziber Buqué & Laurence Zitvogel

  7. Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, 94805, Villejuif, France

    Oliver Kepp & Guido Kroemer

  8. INSERM, U1015, 94805, Villejuif, France

    Laurence Zitvogel

  9. Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, 94805, Villejuif, France

    Laurence Zitvogel

  10. Université Paris Sud/Paris XI, 94270, Le Kremlin-Bicêtre, France

    Laurence Zitvogel

  11. Department of Women's and Children's Health, Karolinska Institute, Karolinska University Hospital, 17176, Stockholm, Sweden

    Guido Kroemer

  12. Pôle de Biologie, Hopitâl Européen George Pompidou, AP-HP, 75015, Paris, France

    Guido Kroemer

Authors
  1. Lorenzo Galluzzi
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  2. Aitziber Buqué
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  3. Oliver Kepp
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  4. Laurence Zitvogel
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  5. Guido Kroemer
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Corresponding authors

Correspondence to Lorenzo Galluzzi or Guido Kroemer.

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PowerPoint slides

Glossary

Microorganism-associated molecular patterns

(MAMPs). Conserved microbial components that, upon detection by the host, can favour the establishment of immunological tolerance or promote a state of accrued resistance to infection.

Damage-associated molecular patterns

(DAMPs). Endogenous molecules that are normally invisible to the host immune system but, once emitted by stressed or dying cells, initiate danger signalling.

Checkpoint blockers

Clinically used monoclonal antibodies that instate (or reinstate) anticancer immunosurveillance by inhibiting immunosuppressive receptors like cytotoxic T lymphocyte associated protein 4 (CTLA4) or programmed cell death 1 (PDCD1; also known as PD1).

Unfolded protein response

(UPR). Stress-responsive mechanism that increases the ability of the endoplasmic reticulum to cope with an increased load of unfolded polypeptides.

Cytosolic DNA sensors

Intracellular PRRs including Z-DNA binding protein 1 (ZBP1; also known as DAI) that are involved in the detection of cytosolic double-stranded DNA.

RIG-I-like receptors

Intracellular PRRs resembling DEAD box protein 58 (DDX58; also known as RIG-I) that are involved in the detection of cytosolic double-stranded RNA.

NOD-like receptors

Intracellular PRRs involved in the detection of a wide panel of MAMPs of both bacterial and viral origin.

Inflammasome

Large supramolecular platform responsible for the activation of caspase 1 and consequent proteolytic maturation of IL-1β and IL-18.

Photodynamic therapy

(PDT). A treatment for pre-malignant and malignant skin conditions, based on the administration of a drug that operates as a photosensitizer followed by exposure to a particular type of light.

Accidental necrosis

A form of cell death that cannot be modulated by pharmacological or genetic interventions, invariably manifesting with necrotic morphological features.

Abscopal effect

Immunological response to radiation therapy whereby the irradiation of a malignant lesion results in the regression or stabilization of a distant, non-irradiated lesion.

Z-VAD-fmk

A chemical agent that inhibits a wide panel of proteolytic enzymes, including several caspases and calpains.

SMAC mimetic

A chemical agent that resembles second mitochondria-derived activator of caspase (SMAC; also known as DIABLO) in its ability to inhibit various members of the inhibitor of apoptosis (IAP) protein family.

BCL-2 protein family

A large group of proteins sharing one to four B cell lymphoma 2 (BCL-2) homology (BH) domains, which play a crucial role in the regulation of some variants of apoptotic cell death.

Necrosome

An amyloid-like supramolecular platform that precipitates necroptosis by allowing for the physical and functional interaction between RIPK1, RIPK3 and MLKL.

Antigen spreading

Immunological phenomenon whereby the antigenic targets of an adaptive immune response expand and diversify over time, presumably as a consequence of sustained cell death and DAMP signalling.

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Galluzzi, L., Buqué, A., Kepp, O. et al. Immunogenic cell death in cancer and infectious disease. Nat Rev Immunol 17, 97–111 (2017). https://doi.org/10.1038/nri.2016.107

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