View metadata, citation and similar papers at core.ac.uk brought to you by CORE

provided by Enlighten

REVIEW Targeting immunogenic cell in Asma Ahmed1,2 and Stephen W.G. Tait1,2

1 Cancer Research UK Beatson Institute, Glasgow, UK 2 Institute of Cancer Sciences, University of Glasgow, UK

Keywords Immunogenic (ICD) is a type of cancer cell death triggered by cancer; caspase; cell death; DAMPs; certain chemotherapeutic drugs, oncolytic , physicochemical thera- ; interferon pies, , and radiotherapy. It involves the activation of the immune system against cancer in immunocompetent hosts. ICD com- Correspondence A. Ahmed and S. W. G. Tait, Cancer prises the release of damage-associated molecular patterns (DAMPs) from Research UK Beatson Institute, Garscube dying tumor cells that result in the activation of tumor-specific immune Estate, Switchback Road, Glasgow, G61 responses, thus eliciting long-term efficacy of anticancer drugs by combin- 1BD, UK ing direct cancer cell killing and antitumor immunity. Remarkably, subcu- E-mails: taneous injection of dying tumor cells undergoing ICD has been shown to [email protected]; provoke anticancer vaccine effects in vivo. DAMPs include the cell surface [email protected] exposure of (CRT) and heat-shock (HSP70 and (Received 24 August 2020, accepted 9 HSP90), extracellular release of (ATP), high-mobil- November 2020, available online 28 ity group box-1 (HMGB1), type I IFNs and members of the IL-1 cytokine November 2020) family. In this review, we discuss the cell death modalities connected to ICD, the DAMPs exposed during ICD, and the mechanism by which they doi:10.1002/1878-0261.12851 activate the immune system. Finally, we discuss the therapeutic potential and challenges of harnessing ICD in cancer .

1. Introduction entity induced by certain chemotherapeutic drugs, oncolytic viruses, physicochemical therapies, photody- Immunogenic cell death (ICD) is a form of regulated namic therapy, and radiotherapy [1,2]. Recently, cell death (RCD) that is sufficient to activate an adap- Legrand et al. proposed to define ICD on the basis of tive in an immunocompetent setting the communication between dying and immune cells as [1]. It has been classified as a distinct poorly defined a successful dialog between a dying cell and an

Abbreviations ATP, adenosine triphosphate; BAK, BCL-2 homologous antagonist killer; BAX, BCL-2-associated X ; BCL-2, B-cell lymphoma 2; BID, BH3-interacting domain death agonist; c-FLIP, cellular FLICE-like inhibitory protein; cGAMP, cyclic guanosine monophosphate–adenosine monophosphate; cGAS, cyclic GMP-AMP synthase; CRT, calreticulin; CXCL10, chemokine C-X-C motif ligand 10; DAMPs, damage- associated molecular patterns; DCs, dendritic cells; DISC, death-inducing signaling complex; ER, ; FADD, FAS- associated protein with death domain; FASL, FAS ligand; GSDMD, gasdermin D; GSDMDNT, N-terminal fragment of gasdermin D; GSDME, gasdermin E; HMGB1, high-mobility group box-1; HSP, heat-shock proteins; Hyp-PDT, hypericin-based photodynamic therapy; ICD, immunogenic cell death; IFN, interferon; IFNAR, IFN-a and IFN-b receptors; IL, interleukin; IRF3, interferon regulatory factor 3; ISGs, IFN- stimulated ; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; MHC, major histocompatibility complex; MLKL, mixed- lineage kinase-like; MOMP, mitochondrial outer membrane permeabilization; mtDNA, mitochondrial DNA; NF-jB, nuclear factor kappa-light- chain-enhancer of activated B cells; NK cells, natural killer cells; NLR, NOD-like receptor; NLRP3, NOD-like receptor family, - containing 3 protein; P2RX7, purinergic receptor P2X 7; PD-L1, programmed death ligand; PRRs, pattern recognition receptors; PS, phosphatidyl serine; RCD, regulated cell death; RIPK1, receptor-interacting serine/threonine protein kinase 1; RIPK3, receptor-interacting serine/threonine protein kinase 3; ROS, ; STING, stimulator of interferon genes; tBID, truncated form of BID; TBK1, TANK-binding kinase 1; TLR, Toll-like receptor; TNF, tumor necrosis factor; TRAIL, TNF-related -inducing ligand; ZBP, Z-DNA- binding protein.

2994 Molecular Oncology 14 (2020) 2994–3006 ª 2020 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. A. Ahmed and S. W. G. Tait Immunogenic cell death and cancer therapy appropriately disposed immune system [3]. Neverthe- Intrinsic apoptosis is triggered by perturbation in the less, the molecular mechanisms of this interaction are environment involving DNA damage, endoplasmic yet to be defined. The long-standing idea that the reticulum (ER) stress, excessive reactive oxygen species immune system functions by merely making a distinc- (ROS) formation, and replication stress. The key event tion between self and non-self has been revised with the for intrinsic apoptosis is mitochondrial outer mem- introduction of the danger model that posits a model in brane permeabilization (MOMP) [11], that is regulated which our immune system responds to entities that by the interactions between the pro-apoptotic and the cause damage as opposed to those that are simply for- anti-apoptotic B-cell lymphoma 2 (BCL-2) family eign [4]. Dying or stressed cells release molecules that members [12]. The pro-apoptotic proteins BCL-2-asso- can function as either adjuvants or danger signals for ciated X (BAX) and BCL-2 homologous antagonist the immune system. These signals are collectively called killer (BAK) permeabilize the mitochondrial outer damage-associated molecular patterns (DAMPs) [5]. membrane; subsequently, cytochrome c and other sol- Importantly, ICD encompasses the release of DAMPs uble proteins are released from the mitochondrial from dying tumor cells, that are recognized by innate intermembrane space resulting in caspase activation pattern recognition receptors (PRRs), such as Toll-like and cell death (Fig. 1) [11]. receptors (TLRs) and NOD-like receptors (NLRs) Extrinsic apoptosis is engaged following binding of resulting in the activation of tumor-specific immune death ligands including FAS ligand (FASL), tumor responses, thus provoking long-term efficacy of anti- necrosis factor (TNF), or TNF-related apoptosis-in- cancer drugs by combining direct cancer cell killing and ducing ligand (TRAIL) to their cognate receptors, antitumor immunity, generally associated with immuno- FAS, TNFRSF1A, and TNFRSF10A and logical memory [1,2]. Herein, we discuss different stim- TNFRSF10B receptors, respectively [3]. FAS and uli of ICD, the role of DAMPs in T-cell cross-priming, TRAIL induce the assembly of the death-inducing sig- and the activation of antitumor immune response. naling complex (DISC), whereas TNF ligation induces Finally, we discuss future perspectives for therapeutic complex I and complex II. These complexes function targeting of ICD in cancer therapy. as a platform to regulate caspase-8 activation [1]. The DISC is composed of FAS-associated protein with 2. of cell death death domain (FADD), caspase-8, and cellular pathways FLICE-like inhibitory protein (c-FLIP) [3]. In contrast to FAS and TRAIL, the primary signaling output of Accumulating evidence has shown that dying cells TNF is not death but rather cell survival via complex actively regulate immune responses as they release or I that induces the activation of nuclear factor kappa- expose molecules that serve as danger signals to stimu- light-chain-enhancer of activated B cells (NF-jB) and late the . Nonetheless, the inter- mitogen-activated protein kinase (MAPK). This ulti- action between cell death trigger and the downstream mately leads to the production of inflammatory cytoki- molecular pathways that determines cell death nes and prosurvival proteins such as c-FLIP. The immunogenicity is highly complex [3,6]. Here, we dis- receptor-interacting serine/threonine protein kinase 1 cuss the cell death pathways commonly described to (RIPK1) is a key signaling molecule that actively induce an immune response, focusing on apoptosis, determines the balance between inflammation and cell , and (Fig. 1). Other cell death survival, apoptosis, and necroptosis, a form of cas- modalities are extensively reviewed elsewhere [1]. pase-independent RCD (Fig. 1) [13]. TNF-induced cell death is tightly regulated by several checkpoints. Upon removal of these brakes, complex II is formed com- 2.1. Apoptosis prising RIPK1, FADD, caspase-8, and c-FLIP. For- Apoptosis is a form of RCD important for develop- mation of complex II leads to the activation of ment, tissue homeostasis, and immunity [7]. During caspase-8 that activates caspase-3 and caspase-7 and apoptosis, cells undergo cytoplasmic shrinkage, nuclear mediates the crosstalk between intrinsic apoptosis and fragmentation, chromatin condensation, and plasma extrinsic apoptosis by cleaving pro-apoptotic BH3 membrane blebbing followed by the formation of interacting domain death agonist (BID). The active apoptotic bodies that are efficiently and rapidly cleared truncated form of BID (tBID) then activates BAX and by [8–10]. Apoptosis is mediated by the BAK and effectively triggers MOMP (Fig. 1) [13]. activity of caspase proteases and can be engaged by Although MOMP is critical for intrinsic apoptosis, two modes: intrinsic and extrinsic, both converge upon caspases are not, as typically cells die post-MOMP in activation of caspase-3 and caspase-7 (Fig. 1) [11]. the absence of caspase activity. Caspases appear to

Molecular Oncology 14 (2020) 2994–3006 ª 2020 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of 2995 Federation of European Biochemical Societies Immunogenic cell death and cancer therapy A. Ahmed and S. W. G. Tait

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 1b (IL-1b) and IL-18 into their mature form that are released by GSDMD pores. function primarily to accelerate cell death—this serves strongly provokes ICD through the activation of NF- important functions during development and keeps jB and the induction of mitochondrial DNA apoptosis immunologically silent [14–17]. For example, (mtDNA)-mediated type I IFN responses [14,16,17].In apoptotic caspases cleave and inactivate cyclic GMP- line with this, caspase inhibition has been shown to AMP synthase (cGAS) and interferon regulatory fac- induce antitumor activities accompanied by tumor tor 3 (IRF3) to suppress type I interferon (IFN) regression [14]. Furthermore, emricasan, a pan caspase response [18]. Caspases also inactivate DAMPs indi- inhibitor, synergizes with radiation and the immune rectly such as high-mobility group box-1 (HMGB1) checkpoint inhibitor, anti-programmed death ligand [19]. Thus, engaging MOMP while blocking caspases (PD-L1), to induce systemic antitumor effects [20].

2996 Molecular Oncology 14 (2020) 2994–3006 ª 2020 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies A. Ahmed and S. W. G. Tait Immunogenic cell death and cancer therapy

While most of anticancer therapies induce apoptosis, that oncolytic -mediated induction of RIPK3 only a few do so in immunogenic way [21]. Those expression in tumor cells conferred durable tumor include [22], , oncolytic clearance and an abscopal effect [29]. Thus, targeting viruses, radiotherapy, and photodynamic therapy necroptosis represents an attractive therapeutic [2,23]. Such therapies are proposed to act by inducing approach in cancer therapy especially in apoptosis-re- the release of DAMPs in addition to cell death [1]. sistant tumors. Remarkably, subcutaneous injection of cancer cells treated with the aforementioned therapies induces a 2.3. Pyroptosis potent cancer vaccine effect [5,23,24]. Pyroptosis is a lytic pro-inflammatory form of RCD culminating with the formation of plasma membrane 2.2. Necroptosis pores by members of the gasdermin protein family, Necroptosis is a lytic form of RCD that requires the primarily gasdermin D (GSDMD), as a consequence activation of the kinases RIPK1 and RIPK3, which of inflammatory caspase activation (Fig. 1). Inflamma- assemble into the necrosome. Necroptosis is initiated tory caspases are comprised of caspase-1, caspase-4, by death receptors including TNF, PRRs such as and caspase-5 in human, and caspase-1 and caspase-11 TLR3 that sense viral nucleic acids, TLR4 detecting in mice. Primarily pyroptosis is observed in monocytes bacterial lipopolysaccharide (LPS), and the activation and but can also occur in epithelial cells of the intracellular sensor Z-DNA-binding protein, [31,32]. Caspase-1 activation is initiated by ligands of ZBP (also known as DAI), that senses cytoplasmic canonical inflammasomes, which are signaling com- viral proteins. Necroptosis downstream TNF signaling plexes assembled upon detection of host or pathogen- requires inhibition of caspase-8 in complex II resulting derived danger signals (Fig. 1). Instead, cytosolic bac- in the activation of RIPK3 by RIPK1 [13,21,25,26]. terial LPS can directly activate caspase-4 and caspase- Once activated, RIPK3 phosphorylates mixed-lineage 5 in humans or caspase-11 in mice [33]. These caspases kinase-like (MLKL) leading to its oligomerization at cleave GSDMD liberating an N-terminal fragment the plasma membrane, causing rapid membrane per- (GSDMDNT), which has intrinsic pore-forming activity meabilization (Fig. 1) and the subsequent release of resulting in pyroptosis and the release of DAMPs immunogenic DAMPs that robustly activate the innate (Fig. 1) [31,33]. Caspase-8 can also cleave GSDMD and adaptive immune systems [25,27,28]. following apoptotic stimulation [34], whereas GSDME In contrast to apoptotic and lytic necrotic cells, is cleaved by caspase-3 and caspase-8 to induce pyrop- necroptotic dying cells mediate DAMP release, tosis either directly or secondary to apoptosis increase uptake by phagocytes, and induce [31,35,36]. Of note, GSDME is silenced in most can- (DC) maturation leading to efficient cers but expressed in normal tissue. Thus, GSDME-in- CD8+ T-cell cross-priming, a functional outcome of duced pyroptosis has been proposed to underly the antigen cross-presentation, whereby antigen-specific toxicity of drugs [36]. Intriguingly, na€ıve CD8+ T cells are activated to become cytotoxic restoration of GSDME expression in cancer cells sup- T lymphocytes, and antitumor immunity. These effects presses tumor growth mediated by enhancing the require RIPK3 and RIPK1-mediated induction of NF- phagocytosis of tumor cells by tumor-associated jB but not DAMP release [29,30]. Conversely, another macrophages and the activation of tumor-infiltrating study demonstrated that immunogenicity of necrop- natural killer (NK) and CD8+ T cells [37]. Moreover, totic cells does not correlate with the extent of NF-jB the activation of pyroptosis in tumor cells induces but rather with DAMP release [27]. Hence, although it effective antitumor immunity that synergizes with anti- becomes apparent that RIPK1 and RIPK3 are PD1 immune checkpoint blockade [38]. required for necroptotic cell immunogenicity, the Interestingly, the GSDMENT can localize to mito- underlying mechanisms are controversial. chondria and induce MOMP. Likewise, the inflamma- Due to the immunogenic nature of necroptosis, some-generated GSDMDNT can permeabilize mito- necroptotic cells have been effectively used to induce chondria linking inflammasome activation to apopto- potent antitumor activity and tumor vaccination sis. These data underscore a role of pyroptosis in [27,29,30]. Consistent with this notion, high expression inducing MOMP to enhance apoptosis [39]. Active levels of RIPK3 in melanoma patients correlated with caspase-1 and caspase-8 process the pro-inflammatory improved patient survival [29]. Moreover, RIPK3 cytokines interleukin 1b (IL-1b) and IL-18 into their expression is lost in many cancer cell lines and in pri- mature form. Once matured, they are released by mary human [27]. Recently, it has been shown GSDMD and GSDME pores (Fig. 1) [3,40]. Of note,

Molecular Oncology 14 (2020) 2994–3006 ª 2020 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of 2997 Federation of European Biochemical Societies Immunogenic cell death and cancer therapy A. Ahmed and S. W. G. Tait the activation of the NLR family, pyrin domain-con- 3.1. Type I IFNs and IL-1 family cytokines taining 3 protein (NLRP3) inflammasome, can cause GSDMD-mediated IL-1 b release from living macro- The rapid production of type I IFNs contributes to phages indicating a nonpyroptotic role of GSDMD the anticancer effects of certain chemotherapeutics [41]. [45]. Cancer cells succumbing to ICD produce type I IFNs through the activation of TLR3 by self-RNA 3. DAMPS: mediators of emitted from dying cells [45] or the cGAS/STING immunogenicity pathway in response to mtDNA release [46]. Hence, the degradation of extracellular nucleic acids that Upon induction of ICD, dying tumor cells release or result in their reduced sensing by phagocytes such as expose DAMPs (Fig. 2). Yatim et al. classified DCs, , and macrophages, considerably lim- DAMPs as constitutive DAMPs (cDAMPs), which are its the immunogenicity of RCD. Type I IFNs mediate immune-stimulatory endogenous molecules that are broad immunostimulatory effects on the aforemen- constitutively expressed before death and are released tioned immune cells [1]. Additionally, by binding to by dying cells, and inducible DAMPs (iDAMPs), IFN-a and IFN-b receptors (IFNAR I) on cancer which are the endogenous molecules within dying cells cells, type I IFNs trigger autocrine and paracrine sig- generated during cell death via mechanisms that are naling pathways culminating in the expression and dependent on the underlying cell death pathway [6]. release of IFN-stimulated genes (ISGs) including the DAMPs include nucleic acids such as mtDNA detected T-cell chemoattractant chemokine C-X-C motif ligand by cGAS and stimulator of interferon genes (STING) 10 (CXCL10). Therefore, tumors lacking Tlr3 or Ifnar pathway, the cell surface exposure of ‘eat me’ signals I failed to respond to chemotherapy [45]. Moreover, a such as calreticulin (CRT) and heat-shock proteins type I IFN-related signature predicted clinical (HSP70 and HSP90) that promote the cell uptake by responses to -based chemotherapy and APCs, extracellular release of immunostimulatory fac- correlated with improved survival in patients with tors including adenosine triphosphate (ATP), HMGB1, breast carcinoma characterized by poor prognosis and cytokines such as type I IFNs and IL-1 family [45,47]. (Fig. 2) [2,24,42–44]. Members of the IL-1 cytokine family are powerful Of note, many ICD inducers induce multiple iDAMPs. These cytokines interact with surface recep- DAMPs, for example, anthracyclines, radiotherapy, tors expressed in wide range of cells, including and Hyp-PDT provoke ICD via inducing the surface immune, endothelial, and epithelial cells [44]. All these exposure of CRT and HSPs, the secretion of ATP and cell types can produce and secrete IL-1 cytokines in HMGB1, and the release of mtDNA that stimulates response to infection, trauma, or NF-kB activation to the production of type I IFNs (Fig. 2) [2]. stimulate various immune responses. Therefore, the

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.

2998 Molecular Oncology 14 (2020) 2994–3006 ª 2020 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies A. Ahmed and S. W. G. Tait Immunogenic cell death and cancer therapy

IL-1 cytokine family appears to act as one of the last death, ATP release can occur secondary to caspase-3- signals that alerts the immune system for the presence or caspase-7-mediated activity. Additionally, the opti- of dying cells [3]. An accumulating body of evidence mal release of ATP from dying cells has been shown suggests that various stimuli that induce inflammatory to require . Consequently, genetic or phar- responses to necrotic cell death act through releasing macological inhibition of autophagy strongly reduces IL-1 family members, including ATP. Administration ATP secretion from dying cancer cells and dampens of purified IL-1 family cytokines in vivo is capable of their immunogenicity [49]. Following chemotherapy, promoting the synthesis and secretion of numerous ATP released is sensed by purinergic P2RX7 receptors additional cytokines and chemokines to promote on DCs and induces their recruitment. ATP also medi- recruitment and the production of inflam- ates immunostimulatory effects by activating the matory responses [44]. In line with this notion, neutral- NLRP3 inflammasome and the subsequent secretion of izing antibodies to IL-1 receptor or IL-1b blunt the IL-1b. This step is mandatory for the DC-mediated therapeutic response of tumors to chemotherapy immunogenicity of cell death. Hence, oxaliplatin-trea- in vivo by reducing T-cell priming [43]. Consistently, ted tumor cells failed to prime T cells for IFN-c pro- IL-1a has been shown to enhance the antitumor effi- duction when they were inoculated into P2rx7 cacy of the epidermal growth factor inhibitor, cetux- receptor-deficient hosts. Furthermore, anthracycline- imab, in head and neck squamous cell carcinoma treated breast cancer patients carrying a loss-of-func- patients [48]. tion allele of P2RX7 developed metastatic disease more rapidly than individuals carrying the normal allele [43]. 3.2. Calreticulin Calreticulin (CRT) is a soluble protein in the lumen of 3.4. HMGB1 the ER where it mediates several functions. Those include chaperone activity and the regulation of cal- HMGB1 is an abundant nuclear nonhistone chro- cium homeostasis and signaling, proper assembly of matin-binding protein. An important characteristic of major histocompatibility complex (MHC) class I mole- ICD is the release of HMGB1 from the nucleus into cules, and the loading of antigen. Surface exposure of the surroundings of dying cells (Fig. 2). HMGB1 CRT is an important ‘eat me’ signal that interacts with mediates potent pro-inflammatory effects by binding CD91 receptors in phagocytes and enables them to to TLR4 on DCs to stimulate efficient processing and efficiently engulf dead cells [5,49]. In the course of cross-presentation of tumor from dying cells ICD, CRT translocation from the ER occurs before [43,50]. In a tumor vaccination mouse model, using phosphatidyl serine (PS) exposure. This early, pre- HMGB1-depleted tumor cells or neutralizing HMGB1 apoptotic exposure of CRT on the plasma membrane by specific antibodies compromised the ability of mice facilitates the uptake of dying cells by DCs, which lead to resist tumorigenesis. Furthermore, breast cancer to subsequent tumor antigen cross-presentation and patients with a TLR4 loss-of-function allele, that pre- tumor-specific cytotoxic T lymphocyte responses [24]. vents HMGB1 binding to TLR4, are more prone to Consistent with a role of CRT in mediating immuno- relapse after radiotherapy or chemotherapy [50]. genicity of ICD, knockdown of CRT or defects in Besides, another study indicated that HMGB1 syner- CRT exposure pathway abolishes the ability of dying gizes with ATP to induce IL-1b release by DCs and cancer cells succumbing to anthracyclines to establish that antibody specific for HMGB1 abrogated the abil- protective immunity in mice, while the provision of ity of DCs to produce IL-1b in contact with dying exogenous CRT confers immunogenicity of otherwise tumor cells [43]. Taken altogether, these observations nonimmunogenic types of RCD. Accordingly, CRT delineate an important role of HMGB1 for cell death exposure has been shown to have a positive prognostic immunogenicity. However, accumulating evidence value in patients with acute myeloid leukemia [1]. shows that the immunogenic properties of HMGB1 are dependent upon its redox state. This has been shown by the potent pro-inflammatory activities of 3.3. ATP HMGB1-reduced form in contrast to the inactive oxi- Extracellular ATP released from dying cells acts as a dized form [51]. Thereby, caspase-dependent produc- ‘find me’ signal and is required for the generation of tion of ROS that triggers the oxidation of HMGB1 robust chemotherapy-induced antitumor immune has been shown to dampen its immunostimulatory responses. Consequently, ATP depletion abolishes the activity leading to the induction of immunological tol- immunogenicity of cell death [1,5]. Following cell erance of dying cells [19]. In marked contrast, one

Molecular Oncology 14 (2020) 2994–3006 ª 2020 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of 2999 Federation of European Biochemical Societies Immunogenic cell death and cancer therapy A. Ahmed and S. W. G. Tait study has shown that HMGB1 interacted with tumor- immunogenicity of poor ICD inducer chemotherapeu- infiltrating DCs to suppress nucleic acid-mediated anti- tics such as cisplatin [58], etoposide, and mitomycin C tumor activity in mice with established tumors [52]. [24]. The importance of ROS was evident by the Nevertheless, since this immunosuppressive effect of diminished immunogenicity of ICD in the presence of HMGB1 is observed in established tumors where the antioxidants [5]. Importantly, ROS-mediated ER stress tumor environment is likely to contain high levels of induced by Hyp-PDT has been shown to induce the ROS [53], it could be that the inactive oxidized form emission of multiple DAMPs ultimately leading to of HMGB1 is responsible for the observed tolerogenic protective antitumor immune responses [42]. This is effects in this scenario. because hypericin is an ER-localizing drug that causes massive production of ROS at the ER when excited by light of a specific wavelength leading to focused ROS- 3.5. HSPs based ER stress [5]. Intracellular HSPs are highly conserved proteins that have strong cytoprotective and anti-apoptotic proper- 5. T-cell priming and antitumor ties. They behave as molecular chaperones for other immune responses following ICD cellular proteins [54]. One of the first reports that described the role of immunogenicity of cell death in The innate immune system plays a crucial role in the the efficacy of anticancer therapy emerged from the activation of adaptive immunity leading to tumor- observation that induction of HSP expression in specific immune responses. Consistent with this, har- response to cell death increased tumor cell immuno- nessing innate immunity has proven to be highly effec- genicity and conferred enhanced clearance of tumors tive in controlling tumor growth and promoting in vivo [55]. Subsequent studies demonstrated the cell responses to immune checkpoint inhibitors, that surface exposure of HSP70 following Hyp-PDT [23] unleash effector T cells, in a variety of preclinical and and HSP90 after chemotherapy leading to an anti- clinical studies (reviewed in ref. [59]). Following ICD, cancer immune response [56]. Thus, blocking HSP90 DAMPs stimulate PRRs on macrophages, DCs, and abolished chemotherapy-mediated antitumoral vacci- NK cells leading to T-cell activation and the initiation nation [56]. Furthermore, the chemotherapy-induced of immune responses [6]. In order for cell death to increased surface expression of HSP70 and HSP90 in provoke an immune response, the dying cell needs to dying tumor cells correlated with DC activation. How- trigger a total of five steps (Fig. 3). The cell death ever, this DC activation induced by chemotherapy was event itself is considered signal À1, while the release of completely abolished upon pretreatment of these DAMPs and their recognition by PRRs constitutes sig- tumor cells with neutralizing antibodies against the nal 0 [3,6]. DAMPs mediate the attraction of phago- HSP70 and HSP90 and CRT common receptor, CD91 cytes that engulf and process dying cells to present [57]. their antigens on the surface of antigen-presenting cells such as DCs (Fig. 3). Activated DCs migrate to drain- 4. Endoplasmic reticulum (ER) stress ing lymphoid organs where they maturate and encoun- and ICD induction ter naive T cells [3,6,60]. Signal 1 comprises antigen recognition mediated through the T-cell receptor and A proposed shared characteristic of ICD inducers is trigged by DCs cross-presentation of tumor antigens their ability to induce ER stress and ROS production on MHC I or MHC II molecules to CD8+ T cells and [2]. Hence, the more focused the ER stress is, the CD4+ T cells, respectively (Fig. 3). Efficient T-cell acti- higher the immunogenicity of cell death is. On this vation requires the engagement of naive T cells with basis, ICD inducers have been classified into type I co-stimulatory receptors on DCs such as CD80 and ICD inducers that prompt secondary or collateral ER CD86 (signal 2). Signal 3 is the additional polarization stress such as anthracyclines and radiotherapy and and differentiation signals delivered from DCs, includ- type II ICD inducers that foster focused ROS-based ing IL-12 or type I IFNs, that are crucial for T-cell ER stress including hypericin-based photodynamic differentiation into a T-cell effector. All these events therapy (Hyp-PDT) and oncolytic viruses, with the lat- eventually lead to priming of tumor-specific CD8+ T ter being more immunogenic [2,5]. The first systematic cells (Fig. 3) [3,6,59]. screening for ICD inducers identified the anthracycline Noteworthy, although DAMPs such as ATP and doxorubicin as efficient inducer through its ability to HMGB1 induce DC maturation and provoke cytokine induce ER stress [24]. Supporting this notion, con- release, they are insufficient for the induction of effec- comitant induction of ER stress restores the tive T-cell cross-priming highlighting the need for

3000 Molecular Oncology 14 (2020) 2994–3006 ª 2020 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies A. Ahmed and S. W. G. Tait Immunogenic cell death and cancer therapy

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 À1 to 3). Signal À1 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-c-producing T cells. further signals [30]. Phagocytes are attracted by ‘find CD8+ T cells. Therefore, the priming of IFN-c-pro- me’ signals that are released by dying cells including ducing CD8+ T cells by dying tumor cells fails in the ATP and NF-jB-induced signals that trigger phago- absence of a functional IL-1 receptor 1 and in Nlrp3- cyte infiltration. Once phagocytes reach the site of tis- deficient or caspase-1-deficient mice unless exogenous sue damage, they recognize ‘eat me’ signals on the IL-1b is provided. Consistent with this finding, surface of dying cells such as PS. In contrast, the sur- tumors established in Nlrp3-deficient or caspase-1-de- face of healthy cells displays ‘don’t eat me’ signals, ficient hosts were not effectively targeted by such as CD47 [6]. Consistently, increased CD47 chemotherapy [43]. In summary, robust antitumor expression on tumor cells prevents DNA sensing in immune responses require the efficient priming of DCs leading to immune evasion. Thus, the inhibition tumor antigen-specific IFN-c-producing CD8+ T cells of CD47 enhances tumor antigen sensing by DCs elic- that mediate tumor clearance. iting effective T-cell priming and tumor rejection in mice [60]. 6. Inflammatory pathways activated As discussed earlier, the therapeutic efficacy of during ICD anticancer largely depends on DCs, which present antigens from dying cancer cells to The NF-jB pathway regulates diverse cellular pro- prime tumor-specific IFN-c-producing T lymphocytes cesses including proliferation and cell survival, cyto- (Fig. 3) [43,60]. Dying tumor cells release ATP, which kine production, antipathogen response, and activates the NLRP3 inflammasome in DCs allowing inflammation. NF-jB is tightly connected to decisions for the secretion of IL-1b, a cytokine which is of life and death, particularly during extrinsic apopto- required for the polarization of IFN-c-producing sis and necroptosis [3,13]. In the context of ICD,

Molecular Oncology 14 (2020) 2994–3006 ª 2020 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of 3001 Federation of European Biochemical Societies Immunogenic cell death and cancer therapy A. Ahmed and S. W. G. Tait uncoupling cell death from NF-jB activation dampens implicating a therapeutic potential for caspase inhibi- the pro-inflammatory response elicited by dying cells tion in cancer therapy. Supporting this idea, engaging and leads to inefficient CD8+ T-cell priming [14,30]. MOMP under caspase-inhibited conditions results in Supporting this notion, robust CD8+ T-cell cross-prim- activation of NF-jB-mediated upregulation of cytoki- ing has been shown to critically require active RIPK1 nes and chemokines that promotes activation of anti- and NF-jB signaling within dying cells, but not the tumorigenic and cytotoxic CD8+ T cells DAMPs released by these cells [30]. Nonetheless, how leading to robust antitumor immune responses culmi- NF-jB activation within dying cells actively regulates nating in tumor regression [14]. Likewise, a recent cross-priming is unknown [6]. study showed that concomitant treatment of mice with The presence of cytosolic DNA either through bac- caspase inhibitor and radiation results in robust antitu- terial or viral infections or cellular damage triggers mor immune responses as a consequence of enhanced robust pro-inflammatory immune responses [61]. Nota- tumor-derived mtDNA-mediated production of type I bly following MOMP, the release of mtDNA into the IFNs [20]. cytosol activates a plethora of innate immune Type I IFNs have long been used for the effective responses, including cGAS-STING that triggers type I treatment of multiple cancers even before their mecha- IFN responses (Fig. 4), TLR9 which activates NF-jB, nism of action was known and proposed to be utilized and inflammasome formation leading to pyroptosis as adjuvant to cancer vaccines [62]. The importance of and the maturation of IL-1b and IL-18 (reviewed in type I IFNs in mediating antitumor immune responses ref. [46]). Cytosolic DNA activates cGAS to form a is evidenced by the fact that blocking type I IFNs and dimeric cGAS-DNA complex, which synthesizes cyclic the deficiency of IFNAR I abrogates tumor rejection guanosine monophosphate–adenosine monophosphate [63]. Type I IFNs stimulate the activation of DCs fol- (cGAMP) from ATP and GTP (Fig. 4). cGAMP in lowing engulfment of apoptotic tumor cells, sustain turn binds and activates the ER membrane protein tumor antigen-bearing DCs survival, and enhance anti- STING that subsequently recruits TANK-binding gen cross-presentation leading to CD8+ T-cell cross- kinase 1 (TBK1). TBK1 phosphorylates and activates priming [64]. The rapid induction of type I IFNs in the transcription factors IRF3 and NF-jB, leading to tumor cells underlines the mechanism of ICD follow- the production of type I IFNs and other cytokines ing anthracycline treatment of multiple cancer cell (Fig. 4) [46,61]. Accumulating evidence demonstrated lines. This effect required signaling via IFNAR I for that apoptotic caspase activity dampens the produc- efficient antitumor immunity [45]. Similarly, the tion of mtDNA-induced type I IFNs [16–18], cGAS-STING-IRF3-type I IFN cascade mediates a

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.

3002 Molecular Oncology 14 (2020) 2994–3006 ª 2020 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies A. Ahmed and S. W. G. Tait Immunogenic cell death and cancer therapy robust antitumor effects following radiation [65]. Thus, Conflict of interest enhancing cGAS-STING signaling leading to type I The authors declare no conflict of interest. IFN production represents a promising therapeutic approach for cancer treatment. Author contributions 7. Conclusions and perspectives AA and SWGT conceived and designed the manu- script. AA wrote the text and prepared the figures, The concept of cancer immunotherapy is to harness and SWGT edited the manuscript. the immune system to elicit antitumor immune response. Accumulating evidence clearly underscored the ability of DAMPs released from dying cells to acti- Peer Review vate specific antitumor immune responses. Under- The peer review history for this article is available at standing the molecular pathways by which certain https://publons.com/publon/10.1002/1878-0261.12851. cancer therapeutics induce DAMPs and activate the host immune system offer the potential to convert nonimmunogenic inducers of cell death to potent ICD References inducers and open the prospect for improving tumor 1 Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam vaccination strategy. Despite tremendous efforts aim- D, Agostinis P, Alnemri ES, Altucci L, Amelio I, ing to characterize ICD, the current knowledge is far Andrews DW et al. (2018) Molecular mechanisms of from being established. Outstanding questions exist: cell death: recommendations of the Nomenclature What makes a certain cell death modality immuno- Committee on Cell Death 2018. Cell Death Differ 25, genic? Similarly, what are the factors affecting the 486–541. immunogenicity of a dying cell? Additionally, since 2 Garg AD, Galluzzi L, Apetoh L, Baert T, Birge RB, most of the ICD research is conducted in cancer cells Bravo-San Pedro JM, Breckpot K, Brough D, Chaurio and tumor vaccination models, it would be of utmost R, Cirone M et al. (2015) Molecular and translational importance to test ICD in more advanced tumor mod- classifications of DAMPs in immunogenic cell death. els such as orthotopic and genetically engineered Front Immunol 6, 588. mouse models to reflect the complexity of human dis- 3 Legrand AJ, Konstantinou M, Goode EF & Meier P ease. Noteworthy, although ICD has been shown in (2019) The diversification of cell death and immunity: several preclinical models, evidence for ICD in human . Mol Cell 76, 232–242. patients is less compelling. Therefore, further research 4 Matzinger P (2002) The danger model: a renewed sense in human patients is needed to investigate the potential of self. Science 296, 301–305. of ICD in clinical settings. Notably, identifying 5 Krysko DV, Garg AD, Kaczmarek A, Krysko O, biomarkers that stratify patients according to their Agostinis P & Vandenabeele P (2012) Immunogenic cell benefit from ICD immunotherapy would be of great death and DAMPs in cancer therapy. Nat Rev Cancer 12 – advantage. Furthermore, it is tempting to speculate , 860 875. that the administration of single or multiple ICD 6 Yatim N, Cullen S & Albert ML (2017) Dying cells inducers, in addition to harnessing innate immunity actively regulate adaptive immune responses. Nat Rev Immunol 17, 262–275. and/or immune checkpoint inhibition, is likely to boost 7 Czabotar PE, Lessene G, Strasser A & Adams JM the antitumor immune responses resulting in abscopal (2014) Control of apoptosis by the BCL-2 protein effect conferring long-term systemic protection from family: implications for physiology and therapy. Nat cancer development. Nevertheless, these assumptions Rev Mol Cell Biol 15,49–63. remain to be tested as the ICD field is actively expand- 8 Arandjelovic S & Ravichandran KS (2015) Phagocytosis ing and special consideration of the dosage and treat- of apoptotic cells in homeostasis. Nat Immunol 16, 907– ment regiments must be kept in mind to avoid 917. toxicities and the emergence of resistance. 9 Savill J & Fadok V (2000) Corpse clearance defines the meaning of cell death. Nature 407, 784–788. Acknowledgments 10 Taylor RC, Cullen SP & Martin SJ (2008) Apoptosis: controlled demolition at the cellular level. Nat Rev Mol The authors’ research is supported by Cancer Research Cell Biol 9, 231–241. UK (C40872/A2014) and Prostate Cancer UK 11 Bock FJ & Tait SWG (2020) Mitochondria as (RIA17-ST2-002). Figures were created with BioRen- multifaceted regulators of cell death. Nat Rev Mol Cell der.com. Biol 21,85–100.

Molecular Oncology 14 (2020) 2994–3006 ª 2020 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of 3003 Federation of European Biochemical Societies Immunogenic cell death and cancer therapy A. Ahmed and S. W. G. Tait

12 Campbell KJ & Tait SWG (2018) Targeting BCL-2 Panaretakis T, Casares N et al. (2007) Calreticulin regulated apoptosis in cancer. Open Biol 8, 180002. exposure dictates the immunogenicity of cancer cell 13 Annibaldi A & Meier P (2018) Checkpoints in TNF- death. Nat Med 13,54–61. induced cell death: implications in inflammation and 25 Grootjans S, Vanden Berghe T & Vandenabeele P (2017) cancer. Trends Mol Med 24,49–65. Initiation and execution mechanisms of necroptosis: an 14 Giampazolias E, Zunino B, Dhayade S, Bock F, Cloix overview. Cell Death Differ 24, 1184–1195. C, Cao K, Roca A, Lopez J, Ichim G, Pro€ıcs E et al. 26 Weinlich R, Oberst A, Beere HM & Green DR (2017) (2017) Mitochondrial permeabilization engages NF-jB- Necroptosis in development, inflammation and disease. dependent anti-tumour activity under caspase Nat Rev Mol Cell Biol 18, 127–136. deficiency. Nat Cell Biol 19, 1116–1129. 27 Aaes TL, Kaczmarek A, Delvaeye T, De Craene B, De 15 Nonomura K, Yamaguchi Y, Hamachi M, Koike M, Koker S, Heyndrickx L, Delrue I, Taminau J, Uchiyama Y, Nakazato K, Mochizuki A, Sakaue- Wiernicki B, De Groote P et al. (2016) Vaccination Sawano A, Miyawaki A, Yoshida H et al. (2013) Local with necroptotic cancer cells induces efficient anti- apoptosis modulates early mammalian brain tumor immunity. Cell Rep 15, 274–287. development through the elimination of morphogen- 28 Linkermann A & Green DR (2014) Necroptosis. N producing cells. Dev Cell 27, 621–634. Engl J Med 370, 455–465. 16 Rongvaux A, Jackson R, Harman CCD, Li T, West 29 Snyder AG, Hubbard NW, Messmer MN, Kofman SB, AP, de Zoete MR, Wu Y, Yordy B, Lakhani SA, Kuan Hagan CE, Orozco SL, Chiang K, Daniels BP, Baker C-Y et al. (2014) Apoptotic caspases prevent the D & Oberst A (2019) Intratumoral activation of the induction of type I interferons by mitochondrial DNA. necroptotic pathway components RIPK1 and RIPK3 Cell 159, 1563–1577. potentiates antitumor immunity. Sci Immunol 4, 17 White MJ, McArthur K, Metcalf D, Lane RM, eaaw2004. Cambier JC, Herold MJ, van Delft MF, Bedoui S, 30 Yatim N, Jusforgues-Saklani H, Orozco S, Schulz O, Lessene G, Ritchie ME et al. (2014) Apoptotic caspases Barreira da Silva R, Reis e Sousa C, Green DR, Oberst suppress mtDNA-induced STING-mediated type I IFN A & Albert ML (2015) RIPK1 and NF- B signaling in production. Cell 159, 1549–1562. dying cells determines cross-priming of CD8+ T cells. 18 Ning X, Wang Y, Jing M, Sha M, Lv M, Gao P, Science 350, 328–334. Zhang R, Huang X, Feng J-M & Jiang Z (2019) 31 Broz P, Pelegrın P & Shao F (2020) The gasdermins, a Apoptotic caspases suppress type I interferon protein family executing cell death and inflammation. production via the cleavage of cGAS, MAVS, and Nat Rev Immunol 20, 143–157. IRF3. Mol Cell 74,19–31.e7. 32 Fritsch M, Gunther€ SD, Schwarzer R, Albert M-C, 19 Kazama H, Ricci J-E, Herndon JM, Hoppe G, Green Schorn F, Werthenbach JP, Schiffmann LM, Stair N, DR & Ferguson TA (2008) Induction of immunological Stocks H, Seeger JM et al. (2019) Caspase-8 is the tolerance by apoptotic cells requires caspase-dependent molecular switch for apoptosis, necroptosis and oxidation of high-mobility group Box-1 protein. pyroptosis. Nature 575, 683–687. Immunity 29,21–32. 33 Shi J, Zhao Y, Wang K, Shi X, Wang Y, Huang H, 20 Han C, Liu Z, Zhang Y, Shen A, Dong C, Zhang A, Zhuang Y, Cai T, Wang F & Shao F (2015) Cleavage Moore C, Ren Z, Lu C, Cao X et al. (2020) Tumor of GSDMD by inflammatory caspases determines cells suppress radiation-induced immunity by hijacking pyroptotic cell death. Nature 526, 660–665. caspase 9 signaling. Nat Immunol 21, 546–554. 34 Orning P, Weng D, Starheim K, Ratner D, Best Z, Lee 21 Messmer MN, Snyder AG & Oberst A (2019) B, Brooks A, Xia S, Wu H, Kelliher MA et al. (2018) Comparing the effects of different cell death programs Pathogen blockade of TAK1 triggers caspase-8– in tumor progression and immunotherapy. Cell Death dependent cleavage of gasdermin D and cell death. Differ 26, 115–129. Science 362, 1064–1069. 22 Fucikova J, Kralikova P, Fialova A, Brtnicky T, Rob 35 Rogers C, Fernandes-Alnemri T, Mayes L, Alnemri D, L, Bartunkova J & Spisek R (2011) Human tumor cells Cingolani G & Alnemri ES (2017) Cleavage of DFNA5 killed by anthracyclines induce a tumor-specific immune by caspase-3 during apoptosis mediates progression to response. Cancer Res 71, 4821–4833. secondary necrotic/pyroptotic cell death. Nat Commun 23 Garg AD, Krysko DV, Vandenabeele P & Agostinis P 8, 14128. (2012) Hypericin-based photodynamic therapy induces 36 Wang Y, Gao W, Shi X, Ding J, Liu W, He H, Wang surface exposure of damage-associated molecular K & Shao F (2017) Chemotherapy drugs induce patterns like HSP70 and calreticulin. Cancer Immunol pyroptosis through caspase-3 cleavage of a gasdermin. Immunother 61, 215–221. Nature 547,99–103. 24 Obeid M, Tesniere A, Ghiringhelli F, Fimia GM, 37 Zhang Z, Zhang Y, Xia S, Kong Q, Li S, Liu X, Apetoh L, Perfettini J-L, Castedo M, Mignot G, Junqueira C, Meza-Sosa KF, Mok TMY, Ansara J

3004 Molecular Oncology 14 (2020) 2994–3006 ª 2020 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies A. Ahmed and S. W. G. Tait Immunogenic cell death and cancer therapy

et al. (2020) Gasdermin E suppresses tumour growth by 50 Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, Ortiz activating anti-tumour immunity. Nature 579, 415–420. C, Criollo A, Mignot G, Maiuri MC, Ullrich E, 38 Wang Q, Wang Y, Ding J, Wang C, Zhou X, Gao W, Saulnier P et al. (2007) Toll-like receptor 4–dependent Huang H, Shao F & Liu Z (2020) A bioorthogonal contribution of the immune system to anticancer system reveals antitumour immune function of chemotherapy and radiotherapy. Nat Med 13, pyroptosis. Nature 579, 421–426. 1050–1059. 39 Rogers C, Erkes DA, Nardone A, Aplin AE, 51 Yang H, Lundback€ P, Ottosson L, Erlandsson-Harris H, Fernandes-Alnemri T & Alnemri ES (2019) Gasdermin Venereau E, Bianchi ME, Al-Abed Y, Andersson U, pores permeabilize mitochondria to augment caspase-3 Tracey KJ & Antoine DJ (2012) Redox modification of activation during apoptosis and inflammasome cysteine residues regulates the cytokine activity of High activation. Nat Commun 10, 1689. Mobility Group Box-1 (HMGB1). Mol Med 18, 250–259. 40 Jorgensen I & Miao EA (2015) Pyroptotic cell death 52 Chiba S, Baghdadi M, Akiba H, Yoshiyama H, defends against intracellular pathogens. Immunol Rev Kinoshita I, Dosaka-Akita H, Fujioka Y, Ohba Y, 265, 130–142. Gorman JV, Colgan JD et al. (2012) Tumor-infiltrating 41 Evavold CL, Ruan J, Tan Y, Xia S, Wu H & Kagan DCs suppress nucleic acid–mediated innate immune JC (2018) The pore-forming protein gasdermin D responses through interactions between the receptor regulates interleukin-1 secretion from living TIM-3 and the alarmin HMGB1. Nat Immunol 13, macrophages. Immunity 48,35–44.e6. 832–842. 42 Garg AD, Krysko DV, Verfaillie T, Kaczmarek A, 53 Tong L, Chuang C-C, Wu S & Zuo L (2015) Reactive Ferreira GB, Marysael T, Rubio N, Firczuk M, oxygen species in redox cancer therapy. Cancer Lett Mathieu C, Roebroek AJM et al. (2012) A novel 367,18–25. pathway combining calreticulin exposure and ATP 54 Lanneau D, Brunet M, Frisan E, Solary E, Fontenay secretion in immunogenic cancer cell death. EMBO J M & Garrido C (2008) Heat shock proteins: essential 31, 1062–1079. proteins for apoptosis regulation. J Cell Mol Med 12, 43 Ghiringhelli F, Apetoh L, Tesniere A, Aymeric L, Ma 743–761. Y, Ortiz C, Vermaelen K, Panaretakis T, Mignot G, 55 Melcher A, Todryk S, Hardwick N, Ford M, Jacobson Ullrich E et al. (2009) Activation of the NLRP3 M & Vile RG (1998) Tumor immunogenicity is inflammasome in dendritic cells induces IL-1b– determined by the mechanism of cell death via dependent adaptive immunity against tumors. Nat Med induction of expression. Nat Med 4, 15, 1170–1178. 581–587. 44 Martin SJ (2016) Cell death and inflammation: the case 56 Zunino B, Rubio-Patino~ C, Villa E, Meynet O, Proics for IL-1 family cytokines as the canonical DAMPs of E, Cornille A, Pommier S, Mondragon L, Chiche J, the immune system. FEBS J 283, 2599–2615. Bereder J-M et al. (2016) Hyperthermic intraperitoneal 45 Sistigu A, Yamazaki T, Vacchelli E, Chaba K, Enot chemotherapy leads to an anticancer immune response DP, Adam J, Vitale I, Goubar A, Baracco EE, via exposure of cell surface heat shock protein 90. Remedios C et al. (2014) Cancer cell–autonomous Oncogene 35, 261–268. contribution of type I interferon signaling to the 57 Cirone M, Di Renzo L, Lotti LV, Conte V, Trivedi P, efficacy of chemotherapy. Nat Med 20, 1301–1309. Santarelli R, Gonnella R, Frati L & Faggioni A (2012) 46 Riley JS & Tait SW (2020) Mitochondrial DNA in Primary effusion lymphoma cell death induced by inflammation and immunity. EMBO Rep 21, e49799. bortezomib and AG 490 activates dendritic cells 47 Rodriguez-Ruiz ME, Buque A, Hensler M, Hensler M, through CD91. PLoS One 7, e31732. Chen J, Bloy N, Petroni G, Sato A, Yamazaki T, 58 Martins I, Kepp O, Schlemmer F, Adjemian S, Tailler Fucikova J et al. (2019) Apoptotic caspases inhibit M, Shen S, Michaud M, Menger L, Gdoura A, abscopal responses to radiation and identify a new Tajeddine N et al. (2011) Restoration of the prognostic biomarker for breast cancer patients. immunogenicity of cisplatin-induced cancer cell OncoImmunology 8, e1655964. death by endoplasmic reticulum stress. Oncogene 30, 48 Espinosa-Cotton M, Rodman Iii SN, Ross KA, Jensen 1147–1158. IJ, Sangodeyi-Miller K, McLaren AJ, Dahl RA, 59 Demaria O, Cornen S, Da€eron M, Morel Y, Medzhitov Gibson-Corley KN, Koch AT, Fu Y-X et al. (2019) R & Vivier E (2019) Harnessing innate immunity in Interleukin-1 alpha increases anti-tumor efficacy of cancer therapy. Nature 574,45–56. cetuximab in head and neck squamous cell carcinoma. 60 Xu MM, Pu Y, Han D, Shi Y, Cao X, Liang H, Chen J Immunother Cancer 7, 79. X, Li X-D, Deng L, Chen ZJ et al. (2017) Dendritic 49 Kroemer G, Galluzzi L, Kepp O & Zitvogel L (2013) cells but not macrophages sense tumor mitochondrial Immunogenic cell death in cancer therapy. Annu Rev DNA for cross-priming through signal regulatory Immunol 31,51–72. protein a signaling. Immunity 47, 363–373.e5.

Molecular Oncology 14 (2020) 2994–3006 ª 2020 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of 3005 Federation of European Biochemical Societies Immunogenic cell death and cancer therapy A. Ahmed and S. W. G. Tait

61 Cai X, Chiu Y-H & Chen ZJ (2014) The cGAS- 64 Lorenzi S, Mattei F, Sistigu A, Bracci L, Spadaro F, cGAMP-STING pathway of cytosolic DNA sensing Sanchez M, Spada M, Belardelli F, Gabriele L & and signaling. Mol Cell 54, 289–296. Schiavoni G (2011) Type I IFNs control antigen 62 Belardelli F, Ferrantini M, Proietti E & Kirkwood JM retention and survival of CD8a + dendritic cells after (2002) Interferon-alpha in tumor immunity and uptake of tumor apoptotic cells leading to cross- immunotherapy. Cytokine Growth Factor Rev 13, priming. J Immunol 186, 5142–5150. 119–134. 65 Deng L, Liang H, Xu M, Yang X, Burnette B, Arina 63 Dunn GP, Bruce AT, Sheehan KCF, Shankaran V, A, Li X-D, Mauceri H, Beckett M, Darga T et al. Uppaluri R, Bui JD, Diamond MS, Koebel CM, (2014) STING-dependent cytosolic DNA sensing Arthur C, White JM et al. (2005) A critical function for promotes radiation-induced type I interferon-dependent type I interferons in cancer immunoediting. Nat antitumor immunity in immunogenic tumors. Immunity Immunol 6, 722–729. 41, 843–852.

3006 Molecular Oncology 14 (2020) 2994–3006 ª 2020 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies