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Tumor Cell Death and ATP Release Prime Dendritic Cells and Efficient Anticancer Immunity

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Tumor Cell Death and ATP Release Prime Dendritic Cells and Efficient Anticancer Immunity Published OnlineFirst January 19, 2010; DOI: 10.1158/0008-5472.CAN-09-3566 Published Online First on January 19, 2010 as 10.1158/0008-5472.CAN-09-3566 Review Cancer Research Tumor Cell Death and ATP Release Prime Dendritic Cells and Efficient Anticancer Immunity Laetitia Aymeric1,2,3, Lionel Apetoh1,2,3, François Ghiringhelli1,2,3,4,5, Antoine Tesniere2,3,6, Isabelle Martins2,3,6, Guido Kroemer2,3,6, Mark J. Smyth7, and Laurence Zitvogel1,2,3 Abstract By destroying tumor cells, conventional anticancer therapies may stimulate the host immune system to elim- inate residual disease. Anthracyclines, oxaliplatin, and ionizing irradiation activate a type of tumor cell death that elicits efficient anticancer immune responses depending on interferon γ (IFNγ)andtheIFNγ receptor. Thus, dying tumor cells emit danger signals that are perceived by dendritic cells (DC), which link innate and cognate immune responses. Recently, we observed that ATP was released by tumor cells succumbing to chemo- therapy. ATP activates purinergic P2RX7 receptors on DC, thus activating the NLRP3/ASC/caspase-1 inflamma- some and driving the secretion of interleukin-1β (IL-1β). IL-1β then is required for the adequate polarization of IFNγ-producing CD8+ T cells. These results imply a novel danger signal, ATP, and a novel receptor, P2RX7, in the chemotherapy-elicited anticancer immune response. Cancer Res; 70(3); 855–8. ©2010 AACR. Setting the Stage Results Some regimens of chemotherapy mediate direct cytotoxic Components of the immune system required for thera- effects on the tumor and, in addition, elicit indirect antitumor peutic effects. Immunosurveillance of tumors involves lym- effects resulting from the immunogenicity of cell death (1, 2). phocytes and requires an intact interferon γ (IFNγ)/IFNγR Anthracyclines, oxaliplatin, and ionizing irradiation can trig- pathway (8–10). To investigate the contribution of these ger immunogenic cell death, whereas many other anticancer immune effectors in the efficacy of chemotherapy, we com- agents fail to do so. We delineated the molecular mechanisms pared chemotherapy-induced tumor growth retardation in underlying the recognition of dying tumor cells by dendritic immunocompetent mice and in mice bearing various immu- − − cells (DC) and found two major checkpoints that dictate nodefects affecting B and/or T cells [Rag / , nu/nu, or wild- the immunogenicity of cell death. First, optimal phagocytosis type (WT) mice treated with a depleting anti-CD8 mAb] or − − − − of chemotherapy or radiotherapy-treated tumor cells by the IFNγ/IFNγR system (Ifng / , IfngR / , or WT treated with DC requires the translocation of endoplasmic reticulum neutralizing anti-IFNγ antibodies). The depletion of CD8+ (ER)-resident calreticulin and disulfide isomerase ERp57 to T cells or the removal of the IFNγ/IFNγR pathway reduced the plasma membrane of dying tumor cells (3–5). Second, the therapeutic effects of oxaliplatin against CT26 colon can- the chromatin-binding high mobility group box 1 protein cer, EL4 thymoma, and abolished the antitumor effects of (HMGB1) must be released by dying tumor cells and must anthracyclines (doxorubicin or mitoxanthrone) against bind to its receptor toll-like receptor 4 (TLR4) on DC to facil- CT26 cells or MCA-induced sarcomas. In contrast, other mo- itate antigen processing of the phagocytic cargo (6). However, lecules such as IL-12Rβ2, perforin, and TRAIL were dispens- additional signals emanating from dying tumor cells are able for the efficacy of these cancer chemotherapies in the same required for the full-blown maturation and differentiation tumor models. Chemotherapy promoted a tumor-specific T-cell of DC and T cells, respectively. Therefore, we addressed the con- response that was detectable in the tumor-draining lymph tribution of damage-associated molecular patterns (DAMP) to nodes (LN), 7 to 10 days after the systemic administration the efficacy of chemotherapy in mouse tumor models (7). of oxaliplatin. After ex vivo restimulation with tumor anti- gens, oxaliplatin-induced CD4+ T cells mainly produced interleukin-2 (IL-2), whereas chemotherapy-induced CD8+ Authors' Affiliations: 1INSERM, U805; 2Institut Gustave Roussy; γ 3Université Paris-Sud, Villejuif, France; 4AVENIR team INSERM CRI- T cells produced high levels of IFN . These chemotherapy- 866; 5Centre Georges Francois Leclerc, Dijon, France; 6INSERM, U848, induced T-cell responses apparently resulted from local can- Villejuif, France; and 7Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia cer cell death because they were detectable in draining LN (but not distant LN) and because dying (but not living) tumor Note: G. Kroemer, M.J. Smyth, and L. Zitvogel share senior co-authorship. cells inoculated in the footpad could mimic these immune Corresponding Author: Laurence Zitvogel, U805 and CIC BT507 IN- SERM, Institut Gustave Roussy, 39 rue Camille Desmoulins, F-94805 effects (7). Villejuif, France. Phone: 33-1-42-11-50-41; Fax: 33-1-42-11-60-94; In conclusion, tumor regression promoted by oxaliplatin or E-mail: [email protected]. anthracyclines elicits a tumor-specific IFNγ-polarized CD8+ doi: 10.1158/0008-5472.CAN-09-3566 T-cell immune response, which is critical for the efficacy of ©2010 American Association for Cancer Research. chemotherapy. www.aacrjournals.org 855 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2010 American Association for Cancer Research. Published OnlineFirst January 19, 2010; DOI: 10.1158/0008-5472.CAN-09-3566 Aymeric et al. The inflammasome NLRP3 is mandatory for the efficacy lease of ATP in vitro from dying tumor cells, by 8 to 20 hours of chemotherapy. Inoculation of anthracycline or oxalipla- postexposure (7, 23). This ATP release became undetectable tin-treated tumor cells in the footpad induced a potent when cells were incubated with the ATP-degrading enzyme IFNγ-polarized CD8+ T-cell response relying on TLR4 signal- apyrase or with inhibitors of ATP synthesis such as antimycin ing in DC (6). We investigated the possible contribution of A plus deoxyglucose (A/D) or the oxidative phosphorylation other receptors for DAMPs that could account for the prim- uncoupler 2,4-dinitrophenol (DNP). When oxaliplatin-treated ing of IFNγ-producing T cells during anticancer chemother- EG7 or anthracycline-treated CT26 cells were admixed with apy. In addition to TLR, NOD-like receptors (NLR) recognize ATP scavengers (A/D, apyrase, DNP) or nonselective P2× re- DAMPs and link inflammation to innate immunity (11, 12). ceptor antagonists (iso-pyridoxalphosphate-6-azophenyl- In macrophages, the so-called “inflammasome” serves as a 2′,5′-disulphonate or oxidized ATP), they lost their capacity central sensor for DAMPs (13). The NLRP3 (CIAS1/CRYO- to elicit protective antitumor immune responses upon subcu- PYRIN)-inflammasome is a multimeric protein complex that taneous inoculation into normal mice. ATP depletion or P2× activates the protease caspase-1, which mediates the proces- receptor blockade also abolished the capacity of oxaliplatin- sing and secretion of pro-inflammatory cytokines (IL-1β, treated EG7 cells [which express the model antigen ovalbu- IL-18, IL-33). The NLRP3 inflammasome can be activated by min (OVA)] to prime OVA-specific cells for IFNγ production endogenous danger signals (DAMPs) or pathogen-associated (7). Altogether, we generalized the finding that dying tumor molecular patterns (PAMP), which all act in concert to induce cells release ATP, which is indispensable for their immunoge- K+ efflux (14–17). Gain-of-function mutations in the human nicity. In contrast, the immunizing capacity of candidate NLRP3 gene cause autoinflammatory disease that can be antigen proteins admixed in TLR adjuvants is not blocked suppressed by the systemic administration of IL-1R antago- by P2× receptor antagonists and hence is likewise indepen- nists (18, 19). To investigate the putative role of the NLRP3 dent of endogenous ATP. inflammasome in anticancer chemotherapy, we compared Because the high affinity receptor for ATP is the purinergic − − tumor growth kinetics of EL4 sarcomas treated with oxalipla- receptor P2RX7, we assessed the ability of p2rx7 / mice to tin in WT mice versus mice deficient in each component of mount a chemotherapy-induced IFNγ polarized CD8+ T-cell the inflammasome [NLRP3, its adaptor molecule apoptosis- response and to control the growth of established tumors associated speck-like protein containing a caspase recruit- after chemotherapy. Importantly, oxaliplatin failed to control − − ment domain (ASC) or caspase-1] or its final product IL-1β. tumor progression in p2rx7 / mice, and, similarly, oxalipla- Each individual player of this complex was required for the tin-treated OVA expressing EG7 could not elicit OVA-specific − − success of chemotherapy. The key contribution of IL-1β in T-cell responses in LN harvested from p2rx7 / mice. Next, the antitumor effects mediated by anthracyclines and/or ox- we showed that host DC were the cells harboring functional aliplatin was also shown in CT26 colon cancer and more P2RX7 receptors during chemotherapy. In transgenic mice importantly in spontaneous tumors induced by MCA (7). expressing the diphtheria toxin receptor on their DC (under To analyze the role of the NLRP3 inflammasome in the the control of the CD11c promoter), diphtheria toxin depletes antitumor immune response elicited by chemotherapy, we LN DC, and this maneuver readily abolishes the CD8+ T-cell inoculated live versus dying tumor cells exposed
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