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Review
. 2014 Jan;21(1):26-38.
doi: 10.1038/cdd.2013.48. Epub 2013 May 17.

Danger signalling during cancer cell death: origins, plasticity and regulation

A D Garg  1 , S Martin, J Golab, P Agostinis
Affiliations
Review

Danger signalling during cancer cell death: origins, plasticity and regulation

A D Garg et al. Cell Death Differ. 2014 Jan.

Abstract

Accumulating data indicates that following anti-cancer treatments, cancer cell death can be perceived as immunogenic or tolerogenic by the immune system. The former is made possible due to the ability of certain anti-cancer modalities to induce immunogenic cell death (ICD) that is associated with the emission of damage-associated molecular patterns (DAMPs), which assist in unlocking a sequence of events leading to the development of anti-tumour immunity. In response to ICD inducers, activation of endoplasmic reticulum (ER) stress has been identified to be indispensable to confer the immunogenic character of cancer cell death, due to its ability to coordinate the danger signalling pathways responsible for the trafficking of vital DAMPs and subsequent anti-cancer immune responses. However, in recent times, certain processes apart from ER stress have emerged (e.g., autophagy and possibly viral response-like signature), which have the ability to influence danger signalling. In this review, we discuss the molecular nature, emerging plasticity in the danger signalling mechanisms and immunological impact of known DAMPs in the context of immunogenic cancer cell death. We also discuss key effector mechanisms modulating the interface between dying cancer cells and the immune cells, which we believe are crucial for the therapeutic relevance of ICD in the context of human cancers, and also discuss the influence of experimental conditions and animal models on these.

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Figures

Figure 1
Figure 1
A schematic representation of the ICD concept in cancer. Cancer cells undergoing ICD expose various danger signals or DAMPs in different stages of apoptosis, including surface-tethered CRT, HSP70 or HSP90; actively or passively secreted ATP; endokines like HMGB1; and end-stage degradation products like nucleic acids. These DAMPs bind their respective receptors like CD91/various scavenger receptors; P2X7R/P2Y2R, TLR2/TLR4/RAGE; and other TLRs on the surface of DCs. These DAMPs along with cancer cell ‘cargo' and antigens cause maturation of DCs, characterized by cell-surface upregulation of MHC-II, CD86, CD83, CD80 and a distinctly pro-inflammatory cytokine pattern (IL-12high, IL-6high, IL-1βhigh, NOhigh and IL-10low/absent). Altogether, these processes cause IL-1β-dependent activation of IL-17-producing γδT cells and increased proliferation of IFN-γ producing CD4+ or CD8+ αβT cells. Such potent T-cell immunity ultimately mediates a number of anti-tumourigenic processes that strive to impede the progression of therapy-resistant residual cancer cells or of an established tumour (in a curative set-up) or challenge by new tumour cells (in a prophylactic set-up). CD, cluster of differentiation; MHC, major histocompatibility complex; NO, nitric oxide; RAGE, receptor for advanced glycation end-products; S.R., scavenger receptors; TLR, Toll-like receptor
Figure 2
Figure 2
Activation of a VRGE profile in cancer cells undergoing ICD. The VRGE programme entails activation of various anti-viral processes like instigation of the type I IFN-regulatory system consisting of transcription factors like, IFN regulatory factor 3 (IRF3), IRF7, IRF5, IRF1, and secretion of IL-1 family cytokines like IL-1β and IL-18., (a) This is an evidence-based network of the proteins whose genes showed an upregulated expression in the CD45-negative cells (predominantly tumour cells) retrieved from a doxorubicin-treated murine tumour, 2 days post treatment. (b) This is an evidence-based network of the proteins whose genes showed an upregulated expression in the T24 human bladder cancer cells retrieved 8 h after hypericin-based photodynamic therapy (Hyp-PDT). The types of evidence behind the network and the corresponding color code scheme are mentioned in the inset. The genes were considered to have role in a viral response based on data available in the GeneCards database version 3.09 (http://www.genecards.org/), wherever applicable. The networks were constructed through the tools available in the STRING database version 9.05 (http://string-db.org/)
Figure 3
Figure 3
A schematic representation of plasticity and regulation of danger signalling and sensing. Various factors like the type of ICD inducers, differences in human and mice immune systems and differences between in vitro and in vivo experimental set-up can all lead to observations of plasticity or regulatory differences in danger signalling and its sensing. For more, please refer to the text. CNX, calnexin; Ecto, surface exposed; KDEL-R, KDEL receptor
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