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  • Review Article
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Immunogenic cell death and DAMPs in cancer therapy

Key Points

  • Damage-associated molecular patterns (DAMPs) are molecules that are secreted, released or surface exposed by dying, stressed or injured cells. DAMPs can function as either adjuvant or danger signals for the immune system. DAMPs such as surface-exposed calreticulin (CRT), secreted ATP and passively released high mobility group protein B1 (HMGB1) are vital for the immunogenic cell death (ICD) of cancer cells.

  • The pathway by which CRT is surface exposed depends on apoptotic stage: one molecular pathway might exclusively execute the trafficking of surface-exposed CRT, or several signalling pathways might coexist, and depending on the cell death stimulus, one signalling pathway could predominate.

  • The trafficking mechanism responsible for the secretion of ATP depends on the apoptotic stage and the type of stress or cell death stimulus that induces it. Moreover, both the mechanisms and the spatiotemporal pattern of ATP secretion from the dying cancer cells might be vital for establishing a suitable extracellular ATP gradient, which is required to engender its chemotactic or DAMP-like functions.

  • Extracellular HMGB1 is vital for the immunogenicity of ICD, but it is also associated with tumour progression. Evidence indicates that the multiple functions of extracellular HMGB1 might be attributed to its different redox states in a context-dependent manner. The in vivo importance of apoptosis-associated HMGB1 release, especially in the context of ICD in established tumours, needs further research.

  • The ability of selected cancer therapies to induce ICD depends on their ability to induce endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) production (either in parallel or in tandem). Both ER stress and ROS production are essential components that instigate the intracellular danger signalling pathways that govern ICD.

  • ICD-associated immunogenicity is more effective if it is fostered by focused ROS-based ER stress (induced by type II ICD inducers such as hypericin-based photodynamic therapy (PDT)) rather than by secondary or collateral ER stress effects (as in the case of certain type I ICD inducers such as mitoxantrone and oxaliplatin).

  • Pre-existing therapy-resistant variants of tumour cells (formed as a result of cancer microevolution) pose an important problem for the therapeutic use of ICD inducers and ICD-associated danger signalling: ideally, ICD-mediating therapies need to overcome hurdles such as therapy-resistant microevolution in cancer. Future research needs to consider a treatment that is based on combinations of ICD inducers that could be applied simultaneously in order to reduce the probability of resistance arising. Alternatively, an ideal ICD inducer could be developed that targets several pathways. Of the current ICD inducers, those that have most of the ideal properties include mitoxantrone, hypericin-PDT, shikonin, cardiac glycosides and bortezomib.

Abstract

Although it was thought that apoptotic cells, when rapidly phagocytosed, underwent a silent death that did not trigger an immune response, in recent years a new concept of immunogenic cell death (ICD) has emerged. The immunogenic characteristics of ICD are mainly mediated by damage-associated molecular patterns (DAMPs), which include surface-exposed calreticulin (CRT), secreted ATP and released high mobility group protein B1 (HMGB1). Most DAMPs can be recognized by pattern recognition receptors (PRRs). In this Review, we discuss the role of endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) in regulating the immunogenicity of dying cancer cells and the effect of therapy-resistant cancer microevolution on ICD.

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Figure 1: The origins of ICD pathways induced by type I and type II ICD inducers.
Figure 2: The molecular trafficking pathways for surface-exposed calreticulin and secreted ATP during the different apoptotic stages.
Figure 3: Comparative overview of the molecular mechanisms responsible for the trafficking of the immunogenic signals, ecto-CRT and ATP.
Figure 4: Immunomodulatory effects of extracellular ATP and extracellular adenosine.

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Acknowledgements

The authors thank A. Bredan for editing the manuscript. This work was supported by project grants from the Fund for Scientific Research Flanders (FWO-Vlaanderen, G.0728.10 to D.V.K.; 3G067512 to D.V.K. and O.K.) and by an individual research grant from FWO-Vlaanderen (31507110 to D.V.K.). D.V.K. is a postdoctoral fellow and A.K. is a doctoral fellow, both paid by fellowships from FWO-Vlaanderen. A.K. is also a recipient of an Emmanuel van der Schueren scholarship from the Flemish league against cancer. Vandenabeele's group is supported by VIB, Ghent University (GROUP-ID Consortium of the UGent MRP initiative), FWO-Vlaanderen (G.0875.11, G.0973.11, G.0A45.12N), Federal Research Programme (IAP 7/32), European Research Programme FP6 ApopTrain (MRTN-CT-035624), FP7 Apo-Sys 200767 and the Euregional PACTII. P.V. holds a Methusalem grant (BOF09/01M00709) from the Flemish Government. Research in Agostinis' group is supported by grants from the KU Leuven (GOA/11/009), Federal Research Programme (IAP 7/32) and FWO-Vlaanderen (G.0661.09; G.0728.10; G.0584.12N). A.D.G. is a postdoctoral fellow supported by the BOF Postdoctoral Mandate (PDM) from KU Leuven (PDMK/12/146).

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Supplementary information

Supplementary information S1

Overview of cell death modalities associated with release or secretion of ATP. (PDF 188 kb)

Glossary

Necrosis

A passive process (often called accidental necrosis) characterized by swelling of the organelles (endoplasmic reticulum and mitochondria) and the cytoplasm, as well as by subsequent destruction of the plasma membrane. Often described in negative terms; for example, by the absence of caspase activation and DNA oligonucleosomal fragmentation.

Apoptosis

Characterized by clear morphological criteria such as decreased cellular volume, chromatin condensation and nuclear fragmentation, and blebbing with the formation of apoptotic bodies containing unchanged organelles.

Hypericin-based PDT

(Hypericin-based photodynamic therapy). An anticancer therapeutic method that uses hypericin, which associates with the endoplasmic reticulum (ER). When activated by light of a suitable wavelength, it causes massive production of reactive oxygen species at the ER. This ultimately culminates in ER stress-mediated, BAX and BAK-based mitochondrial apoptosis.

Ig class switching

A process during which a subset of B cells undergoes class switch recombination, in which the heavy chain constant region is changed to a different immunoglobulin isotype without the introduction of variable region mutations.

Proximal secretory pathway

Denotes the events in the early phase of the secretory pathway, which include packaging of suitable cargo in COPII-coated vesicles, their exit from the endoplasmic reticulum and subsequent fusion of these vesicles with the Golgi complex.

Autophagy

A primary survival mechanism activated in cells subjected to chemical or biological stress and/or nutrient or obligate growth factor deprivation. However, if cellular stress continues, autophagy often becomes associated with features of apoptotic or necrotic cell death.

NALP3–ASC–inflammasome

A multimeric danger-sensing platform that promotes autocatalytic activation of the cysteine protease caspase 1 and mediates the cleavage of inactive pro-interleukin (IL)-1β and IL-18, among other proteins, into their active forms.

Secondary necrosis

A late stage of apoptosis characterized by the loss of plasma membrane integrity. Secondary necrotic cells are often observed in vitro in the absence of phagocytosis, or in some cases in vivo when apoptotic cells cannot be cleared rapidly enough.

Tolerance

A state that involves (active) hypo- or non-responsiveness of innate and adaptive immune cells to a particular biological or chemical entity.

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Krysko, D., Garg, A., Kaczmarek, A. et al. Immunogenic cell death and DAMPs in cancer therapy. Nat Rev Cancer 12, 860–875 (2012). https://doi.org/10.1038/nrc3380

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