A novel pathway combining calreticulin exposure and ATP secretion in immunogenic cancer cell death

Garg, Abhishek D.; Krysko, Dmitri V.; Verfaillie, Tom; Kaczmarek, Agnieszka; Ferreira, Gabriela B; Marysael, Thierry; Rubio, Noemí; Firczuk, Małgorzata; Mathieu, Chantal; Roebroek, Anton; Annaert, Wim; Gołąb, Jakub; Witte, Peter de; Vandenabeele, Peter; Agostinis, Patrizia

doi:10.1038/emboj.2011.497

Cited by 649 publications

(963 citation statements)

References 69 publications

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“…1 Although it has long been considered that apoptotic cell death is tolerogenic, DAMPs have also been found to be released from cells undergoing apoptosis, providing a promising anticancer efficacy. [2][3][4] Therefore, comprehension of ICD induction gradually increases its significance, particularly in the field of cancer immunotherapy.…”

Section: Open Questionsmentioning

confidence: 99%

Multimodal immunogenic cancer cell death as a consequence of anticancer cytotoxic treatments

2013

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Apoptotic cell death generally characterized by a morphologically homogenous entity has been considered to be essentially non-immunogenic. However, apoptotic cancer cell death, also known as type 1 programmed cell death (PCD), was recently found to be immunogenic after treatment with several chemotherapeutic agents and oncolytic viruses through the emission of various danger-associated molecular patterns (DAMPs). Extensive studies have revealed that two different types of immunogenic cell death (ICD) inducers, recently classified by their distinct actions in endoplasmic reticulum (ER) stress, can reinitiate immune responses suppressed by the tumor microenvironment. Indeed, recent clinical studies have shown that several immunotherapeutic modalities including therapeutic cancer vaccines and oncolytic viruses, but not conventional chemotherapies, culminate in beneficial outcomes, probably because of their different mechanisms of ICD induction. Furthermore, interests in PCD of cancer cells have shifted from its classical form to novel forms involving autophagic cell death (ACD), programmed necrotic cell death (necroptosis), and pyroptosis, some of which entail immunogenicity after anticancer treatments. In this review, we provide a brief outline of the well-characterized DAMPs such as calreticulin (CRT) exposure, high-mobility group protein B1 (HMGB1), and adenosine triphosphate (ATP) release, which are induced by the morphologically distinct types of cell death. In the latter part, our review focuses on how emerging oncolytic viruses induce different forms of cell death and the combinations of oncolytic virotherapies with further immunomodulation by cyclophosphamide and other immunotherapeutic modalities foster dendritic cell (DC)-mediated induction of antitumor immunity. Accordingly, it is increasingly important to fully understand how and which ICD inducers cause multimodal ICD, which should aid the design of reasonably multifaceted anticancer modalities to maximize ICD-triggered antitumor immunity and eliminate residual or metastasized tumors while sparing autoimmune diseases.

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Section: Open Questionsmentioning

confidence: 99%

Multimodal immunogenic cancer cell death as a consequence of anticancer cytotoxic treatments

2013

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“…They found that CRT exposure triggered by Hyp-PDT requires reactive oxygen species (as demonstrated with the 1 O 2 quencher L-histidine), class I phosphoinositide-3-kinase (PI3K) activity (as shown with the chemical inhibitor wortmannin and the RNAi-mediated depletion of the catalytic PI3K subunit p110), the actin cytoskeleton (as proven with the actin inhibitor latrunculin B), the ER-to-Golgi anterograde transport (as shown using brefeldin A), the ER stress-associated kinase PERK, the pro-apoptotic molecules BAX and BAK as well as the CRT cell surface receptor CD91 (as demonstrated by their knockout or RNAi-mediated depletion). However, there were differences in the signalling pathways leading to CRT exposure in response to anthracyclines (Panaretakis et al, 2009) and Hyp-PDT (Garg et al, 2012). In contrast to the former, the latter was not accompanied by the exposure of the ER chaperon ERp57, and did not require eIF2a phosphorylation (as shown with non-phosphorylatable eIF2a mutants), caspase-8 activity (as shown with the pancaspase blocker Z-VAD.fmk, upon overexpression of the viral caspase inhibitor CrmA and following the RNAi-mediated depletion of caspase-8), and increased cytosolic Ca 2 þ concentrations (as proven with cytosolic Ca 2 þ chelators and Of note, ATP secretion in response to Hyp-PDT depended on the ER-to-Golgi anterograde transport, PI3K and PERK activity (presumably due to their role in the regulation of secretory pathways), but did not require BAX and BAK (Garg et al, 2012).…”

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confidence: 99%

“…However, there were differences in the signalling pathways leading to CRT exposure in response to anthracyclines (Panaretakis et al, 2009) and Hyp-PDT (Garg et al, 2012). In contrast to the former, the latter was not accompanied by the exposure of the ER chaperon ERp57, and did not require eIF2a phosphorylation (as shown with non-phosphorylatable eIF2a mutants), caspase-8 activity (as shown with the pancaspase blocker Z-VAD.fmk, upon overexpression of the viral caspase inhibitor CrmA and following the RNAi-mediated depletion of caspase-8), and increased cytosolic Ca 2 þ concentrations (as proven with cytosolic Ca 2 þ chelators and Of note, ATP secretion in response to Hyp-PDT depended on the ER-to-Golgi anterograde transport, PI3K and PERK activity (presumably due to their role in the regulation of secretory pathways), but did not require BAX and BAK (Garg et al, 2012). Since PERK can stimulate autophagy in the context of ER stress , it is tempting to speculate that autophagy is involved in Hyp-PDT-elicited ATP secretion, as this appears to be to the case during anthracycline-induced ICD (Michaud et al, 2011).…”

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confidence: 99%

Enlightening the impact of immunogenic cell death in photodynamic cancer therapy

2012

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In this issue of The EMBO Journal, Garg et al (2012) delineate a signalling pathway that leads to calreticulin (CRT) exposure and ATP release by cancer cells that succumb to photodynamic therapy (PTD), thereby providing fresh insights into the molecular regulation of immunogenic cell death (ICD).The textbook notion that apoptosis would always take place unrecognized by the immune system has recently been invalidated Galluzzi et al, 2012). Thus, in specific circumstances (in particular in response to anthracyclines, oxaliplatin, and g irradiation), cancer cells can enter a lethal stress pathway linked to the emission of a spatiotemporally defined combination of signals that is decoded by the immune system to activate tumour-specific immune responses . These signals include the pre-apoptotic exposure of intracellular proteins such as the endoplasmic reticulum (ER) chaperon CRT and the heat-shock protein HSP90 at the cell surface, the preapoptotic secretion of ATP, and the post-apoptotic release of the nuclear protein HMGB1 . Together, these processes (and perhaps others) constitute the molecular determinants of ICD.In this issue of The EMBO Journal, Garg et al (2012) add hypericin-based PTD (Hyp-PTD) to the list of bona fide ICD inducers and convincingly link Hyp-PTDelicited ICD to the functional activation of the immune system. Moreover, Garg et al (2012) demonstrate that Hyp-PDT stimulates ICD via signalling pathways that overlap with-but are not identical to-those elicited by anthracyclines, which constitute the first ICD inducers to be characterized (Casares et al, 2005;Zappasodi et al, 2010;Fucikova et al, 2011).Intrigued by the fact that the ER stress response is required for anthracycline-induced ICD (Panaretakis et al, 2009), Garg et al (2012) decided to investigate the immunogenicity of Hyp-PDT (which selectively targets the ER). Hyp-PDT potently stimulated CRT exposure and ATP release in human bladder carcinoma T24 cells. As a result, T24 cells exposed to Hyp-PDT (but not untreated cells) were engulfed by Mf4/4 macrophages and human dendritic cells (DCs), the most important antigen-presenting cells in antitumour immunity. Similarly, murine colon carcinoma CT26 cells succumbing to Hyp-PDT (but not cells dying in response to the unspecific ER stressor tunicamycin) were preferentially phagocytosed by murine JAWSII DCs, and efficiently immunized syngenic BALB/c mice against a subsequent challenge with living cells of the same type. Of note, contrarily to T24 cells treated with lipopolysaccharide (LPS) or dying from accidental necrosis, T24 cells exposed to Hyp-PDT activated DCs while eliciting a peculiar functional profile, featuring high levels of NO production and absent secretion of immunosuppressive interleukin-10 (IL-10) (Garg et al, 2012). Moreover upon co-culture with Hyp-PDT-treated T24 cells, human DCs were found to secrete high levels of IL-1b, a cytokine that is required for the adequate polarization of interferon g (IFNg)-producing antineoplastic CD8 þ T cells (Aymeric et al, 2010). Taken togethe...

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“…16 In line with this notion, lethal stimuli that fail to elicit sufficient degrees of ER stress (such as mitomycin C and cisplatin) cannot induce the immunogenic exposure of CRT on the cell surface, unless an exogenous source of ER stress is provided. 13,17,18 In contrast, anthracyclines and oxaliplatin are highly efficient at stimulating the PERK-mediated phosphorylation of eIF2a, followed by the caspase-8-mediated cleavage of BCAP31, BAX/BAK activation (presumably at the ER membrane), the anterograde transport of CRT-containing vesicles from the ER to the cell surface (via the Golgi apparatus), and -eventually -the SNAP receptor (SNARE)-dependent fusion of such vesicles with the plasma membrane. 5,16 In response to some (but not all) ICD inducers, protein disulfide isomerase family A, member 3 (PDIA3), an ER reticulum chaperone best known as ERp57, is required for the translocation of (and de facto physically escorts) CRT to the outer leaflet of the plasma membrane.…”

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confidence: 99%

“…5,16 In response to some (but not all) ICD inducers, protein disulfide isomerase family A, member 3 (PDIA3), an ER reticulum chaperone best known as ERp57, is required for the translocation of (and de facto physically escorts) CRT to the outer leaflet of the plasma membrane. 5,16,17 The current literature suggests that the molecular mechanisms accounting for CRT exposure are highly complex and require further in-depth analysis. 17,19,20 Extrareticular CRT is not only of immunological relevance.…”

mentioning

confidence: 99%

Immunogenic calreticulin exposure occurs through a phylogenetically conserved stress pathway involving the chemokine CXCL8

Sukkurwala¹,

Martins²,

Wang³

et al. 2013

Cell Death Differ

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The exposure of calreticulin (CRT) on the surface of stressed and dying cancer cells facilitates their uptake by dendritic cells and the subsequent presentation of tumor-associated antigens to T lymphocytes, hence stimulating an anticancer immune response. The chemotherapeutic agent mitoxantrone (MTX) can stimulate the peripheral relocation of CRT in both human and yeast cells, suggesting that the CRT exposure pathway is phylogenetically conserved. Here, we show that pheromones can act as physiological inducers of CRT exposure in yeast cells, thereby facilitating the formation of mating conjugates, and that a largespectrum inhibitor of G protein-coupled receptors (which resemble the yeast pheromone receptor) prevents CRT exposure in human cancer cells exposed to MTX. An RNA interference screen as well as transcriptome analyses revealed that chemokines, in particular human CXCL8 (best known as interleukin-8) and its mouse ortholog Cxcl2, are involved in the immunogenic translocation of CRT to the outer leaflet of the plasma membrane. MTX stimulated the production of CXCL8 by human cancer cells in vitro and that of Cxcl2 by murine tumors in vivo. The knockdown of CXCL8/Cxcl2 receptors (CXCR1/Cxcr1 and Cxcr2) reduced MTX-induced CRT exposure in both human and murine cancer cells, as well as the capacity of the latter-on exposure to MTX-to elicit an anticancer immune response in vivo. Conversely, the addition of exogenous Cxcl2 increased the immunogenicity of dying cells in a CRT-dependent manner. Altogether, these results identify autocrine and paracrine chemokine signaling circuitries that modulate CRT exposure and the immunogenicity of cell death.

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A novel pathway combining calreticulin exposure and ATP secretion in immunogenic cancer cell death

Cited by 649 publications

References 69 publications

Multimodal immunogenic cancer cell death as a consequence of anticancer cytotoxic treatments

Multimodal immunogenic cancer cell death as a consequence of anticancer cytotoxic treatments

Enlightening the impact of immunogenic cell death in photodynamic cancer therapy

Immunogenic calreticulin exposure occurs through a phylogenetically conserved stress pathway involving the chemokine CXCL8

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