An Immunosurveillance Mechanism Controls Cancer Cell Ploidy

Senovilla, Laura; Vitale, Ilio; Martins, Isabelle; Tailler, Maximilien; Pailleret, Claire; Michaud, Mickaël; Galluzzi, Lorenzo; Adjemian, Sandy; Kepp, Oliver; Niso-Santano, Mireia; Shen, Shensi; Mariño, Guillermo; Criollo, Alfredo; Boilève, Alice; Job, Bastien; Ladoire, Sylvain; Ghiringhelli, François; Sistigu, Antonella; Yamazaki, Takahiro; Rello-Varona, Santiago; Locher, Clara; Poirier-Colame, Vichnou; Talbot, Monique; Valent, Alexander; Berardinelli, Francesco; Antoccia, Antonio; Ciccosanti, Fabiola; Fimia, Gian María; Piacentini, Mauro; Fueyo, Antonio; Messina, Nicole L.; Li, Ming; Chan, Christopher J.; Sigl, Verena; Pourcher, Guillaume; Ruckenstuhl, Christoph; Carmona-Gutiérrez, Didac; Lazar, Vladimir; Penninger, Josef; Madeo, Frank; López-Otı́n, Carlos; Smyth, Mark J.; Zitvogel, Laurence; Castedo, Maria

doi:10.1126/science.1224922

Cited by 376 publications

(367 citation statements)

References 50 publications

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“…CRT exposure was assessed by surface immunostaining and flow cytometry or fluorescence microscopy, as previously described. 3,57 In brief, cells growing on standard supports were collected, washed twice with PBS and fixed in 0.25% paraformaldehyde (w/v in PBS) for 5 min at RT. Alternatively, cells grown on coverslips were washed and similarly fixed.…”

Section: Methodsmentioning

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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Section: Methodsmentioning

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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“…4 Accordingly, there is ample evidence that the long-term fate of breast cancer patients treated with anthracyclines or that of colorectal cancer patients treated with oxaliplatin (OXA) is largely determined by the density of the immune infiltrate (in particular memory effector T cells) at diagnosis, [5][6][7] as well as by dynamic changes in the ratio of cytotoxic T lymphocytes (CTL) versus regulatory T cells occurring shortly after chemotherapy. 8 Loss-of-function alleles of toll-like receptor 4 (TLR4) and formyl peptide receptor 1 (FPR1) also have a negative impact on the therapeutic response of mammary and colorectal carcinoma patients to adjuvant chemotherapies, [9][10][11] further supporting the notion that the immune system dictates (at least part of) the therapeutic response.…”

Section: Introductionmentioning

confidence: 92%

Contribution of RIP3 and MLKL to immunogenic cell death signaling in cancer chemotherapy

Yang¹,

Ma²,

Guo³

et al. 2016

OncoImmunology

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146

145

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Chemotherapy can reinstate anticancer immunosurveillance through inducing tumor immunogenic cell death (ICD). Here, we show that anthracyclines and oxaliplatin can trigger necroptosis in murine cancer cell lines expressing receptor-interacting serine-threonine kinase 3 (RIP3) and mixed lineage kinase domain-like (MLKL). Necroptotic cells featured biochemical hallmarks of ICD and stimulated anticancer immune responses in vivo. Chemotherapy normally killed Rip3 ¡/¡ and Mlkl ¡/¡ tumor cells and normally induced caspase-3 activation in such cells, yet was unable to reduce their growth in vivo. RIP3 or MLKL deficiency abolished the capacity of dying cancer cells to elicit an immune response. This could be attributed to reduced release of ATP and high mobility group box 1 (HMGB1) by RIP3 and MLKL-deficient cells. Measures designed to compensate for deficient ATP and HMGB1 signaling restored the chemotherapeutic response of Rip3 ¡/¡ and Mlkl ¡/¡ cancers. Altogether, these results suggest that RIP3 and MLKL can contribute to ICD signaling and tumor immunogenicity.

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“…2,3,13 Of note, most inducers of apoptosis and necrosis fail to trigger ICD. However, a few chemotherapeutics, including anthracyclines, 7,8 OXA, 14 cyclophosphamide, 15 and -to some extent -microtubular inhibitors, 16 as well as cardiac glycosides, [17][18][19] potently do so. 20,21 Such chemicals appear to be particularly efficient at inducing a pre-mortem endoplasmic reticulum (ER) stress response and autophagy.…”

mentioning

confidence: 99%

Molecular mechanisms of ATP secretion during immunogenic cell death

et al. 2013

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The immunogenic demise of cancer cells can be induced by various chemotherapeutics, such as anthracyclines and oxaliplatin, and provokes an immune response against tumor-associated antigens. Thus, immunogenic cell death (ICD)-inducing antineoplastic agents stimulate a tumor-specific immune response that determines the long-term success of therapy. The release of ATP from dying cells constitutes one of the three major hallmarks of ICD and occurs independently of the two others, namely, the pre-apoptotic exposure of calreticulin on the cell surface and the postmortem release of high-mobility group box 1 (HMBG1) into the extracellular space. Pre-mortem autophagy is known to be required for the ICD-associated secretion of ATP, implying that autophagy-deficient cancer cells fail to elicit therapy-relevant immune responses in vivo. However, the precise molecular mechanisms whereby ATP is actively secreted in the course of ICD remain elusive. Using a combination of pharmacological screens, silencing experiments and techniques to monitor the subcellular localization of ATP, we show here that, in response to ICD inducers, ATP redistributes from lysosomes to autolysosomes and is secreted by a mechanism that requires the lysosomal protein LAMP1, which translocates to the plasma membrane in a strictly caspase-dependent manner. The secretion of ATP additionally involves the caspase-dependent activation of Rho-associated, coiled-coil containing protein kinase 1 (ROCK1)-mediated, myosin II-dependent cellular blebbing, as well as the opening of pannexin 1 (PANX1) channels, which is also triggered by caspases. Of note, although autophagy and LAMP1 fail to influence PANX1 channel opening, PANX1 is required for the ICD-associated translocation of LAMP1 to the plasma membrane. Altogether, these findings suggest that caspase-and PANX1-dependent lysosomal exocytosis has an essential role in ATP release as triggered by immunogenic chemotherapy.

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An Immunosurveillance Mechanism Controls Cancer Cell Ploidy

Cited by 376 publications

References 50 publications

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

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

Contribution of RIP3 and MLKL to immunogenic cell death signaling in cancer chemotherapy

Molecular mechanisms of ATP secretion during immunogenic cell death

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