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Review
. 2020 Dec;14(12):2994-3006.
doi: 10.1002/1878-0261.12851. Epub 2020 Dec 1.

Targeting immunogenic cell death in cancer

Asma Ahmed  1   2 , Stephen W G Tait  1   2
Affiliations
Review

Targeting immunogenic cell death in cancer

Asma Ahmed et al. Mol Oncol. 2020 Dec.

Abstract

Immunogenic cell death (ICD) is a type of cancer cell death triggered by certain chemotherapeutic drugs, oncolytic viruses, physicochemical therapies, photodynamic therapy, and radiotherapy. It involves the activation of the immune system against cancer in immunocompetent hosts. ICD comprises the release of damage-associated molecular patterns (DAMPs) from dying tumor cells that result in the activation of tumor-specific immune responses, thus eliciting long-term efficacy of anticancer drugs by combining direct cancer cell killing and antitumor immunity. Remarkably, subcutaneous injection of dying tumor cells undergoing ICD has been shown to provoke anticancer vaccine effects in vivo. DAMPs include the cell surface exposure of calreticulin (CRT) and heat-shock proteins (HSP70 and HSP90), extracellular release of adenosine triphosphate (ATP), high-mobility group box-1 (HMGB1), type I IFNs and members of the IL-1 cytokine family. In this review, we discuss the cell death modalities connected to ICD, the DAMPs exposed during ICD, and the mechanism by which they activate the immune system. Finally, we discuss the therapeutic potential and challenges of harnessing ICD in cancer immunotherapy.

Keywords: DAMPs; cancer; caspase; cell death; immunogenic cell death; interferon.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
Overview of necroptosis, apoptosis, and pyroptosis signaling pathways. Binding of death ligands such as tumor necrosis factor (TNF) to their cognate receptor (TNFR) leads to pleiotropic signaling including inflammation and cell survival, apoptosis, and necroptosis, determined by the key signaling molecule, the receptor‐interacting serine/threonine protein kinase 1 (RIPK1). Upon inhibition of caspase‐8, RIPK1 activates RIPK3 leading to the formation of the necrosome. The necrosome then phosphorylates and activates mixed‐lineage kinase‐like (MLKL) that causes rapid membrane permeabilization and necroptosis. Activation of caspase‐8 leads to activation of caspase‐3 and caspase‐7 and cell death (extrinsic apoptosis). The intrinsic apoptosis pathway is initiated by perturbation in the internal environment including DNA damage that causes mitochondrial outer membrane permeabilization (MOMP). MOMP is regulated by the interaction between pro‐apoptotic and anti‐apoptotic B‐cell lymphoma 2 (BCL‐2) family proteins. The pro‐apoptotic proteins BCL‐2 associated X (BAX) and BCL‐2 homologous antagonist killer (BAK) form pores at the mitochondrial outer membrane leading to the subsequent release of cytochrome c and the formation of the APAF‐1 apoptosome. The apoptosome activates caspase‐9, which subsequently activates caspase‐3 and caspase‐7 resulting in apoptosis. Caspase‐8 mediates the crosstalk between the intrinsic and extrinsic apoptosis pathways by cleaving the pro‐apoptotic BH3‐interacting domain death (BID) to truncated BID (tBID) that activates BAX and BAK. Damage‐associated molecular patterns (DAMPs) released from dying cells activate pattern recognition receptors such as Toll‐like receptors (TLR). This leads to the activation of canonical inflammasomes that activate caspase‐1. Active caspase‐1 cleaves gasdermin D (GSDMD) liberating an N‐terminal (GSDMDNT) pore‐forming fragment from the C‐terminal (GSDMDC) inhibitory fragment. GSDMDNT form pores leading to membrane permeabilization and pyroptosis. Active caspase‐1 also cleaves the pro‐inflammatory cytokines interleukin 1β (IL‐1β) and IL‐18 into their mature form that are released by GSDMD pores.
Fig. 2
Fig. 2
Characteristics of immunogenic cell death. When tumor cells succumb to immunogenic cell death (ICD) for example following radiotherapy, they release or expose damage‐associated molecular patterns (DAMPs) that stimulate antitumor immune responses. Tumor cells expose the endoplasmic reticulum protein calreticulin (CRT) on their plasma membrane in the pre‐apoptotic stage. They might also expose heat‐shock proteins (HSPs). These factors facilitate the uptake of dying cells by phagocytes. Additionally, tumor cells responding to ICD inducer release adenosine triphosphate (ATP) and the nuclear protein high‐mobility group box‐1 (HMGB1) in the extracellular space. Mitochondrial outer membrane permeabilization enables the release of mitochondrial DNA (mtDNA) into the cytosol.
Fig. 3
Fig. 3
Role of DAMPs in antigen cross‐priming and antitumor immune responses. Upon immunogenic cell death (ICD) induction, dying tumor cells release tumor antigen and damage‐associated molecular patterns (DAMPs). DAMPs stimulate pattern recognition receptors (PRRs) on dendritic cells (DCs) leading to T‐cell activation and the initiation of tumor‐specific antitumor immune responses following five signals (signals −1 to 3). Signal −1 is the cell death process itself that results in DAMPs and provides tumor antigens for antigen cross‐priming. DAMPs mediate the attraction and activation of DCs that engulf and process dying cells (signal 0). DCs provide 3 signals to activate T cells; signal 1 is the antigen recognition mediated through the T‐cell receptor (TCR), trigged by DCs cross‐presentation of tumor antigens on major histocompatibility complex (MHC) I or MHC II molecules to CD8+ T cells and CD4+ T cells, respectively. Signal 2 is the engagement of naive T cells with co‐stimulatory receptors on DCs such as CD80 which is required for efficient T‐cell activation. Signal 3 is the additional polarization and differentiation signals delivered from DCs, including interleukin 12 (IL‐12) or type I interferons (IFNs), that are crucial for T‐cell differentiation into tumor‐specific IFN‐γ‐producing T cells.
Fig. 4
Fig. 4
cGAS‐STING signaling pathway. The presence of cytosolic DNA either through bacterial or viral infections or cellular damage leading to mitochondrial outer membrane permeabilization (MOMP)‐induced mitochondrial DNA (mtDNA) release activates cyclic GMP‐AMP synthase (cGAS). Activated cGAS forms a dimeric cGAS‐DNA complex, which synthesizes cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) from ATP and GTP. cGAMP binds to and activates the endoplasmic reticulum (ER) membrane protein, stimulator of interferon genes (STING), that subsequently recruits TANK‐binding kinase 1 (TBK1). TBK1 phosphorylates and activates the transcription factor interferon regulatory factor 3 (IRF3) leading to the production of type I interferons.
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