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Activation of the NLRP3 Inflammasome in Dendritic Cells Induces IL-1Β–Dependent Adaptive Immunity Against Tumors

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Activation of the NLRP3 Inflammasome in Dendritic Cells Induces IL-1Β–Dependent Adaptive Immunity Against Tumors A RTICLES Activation of the NLRP3 inflammasome in dendritic cells induces IL-1β–dependent adaptive immunity against tumors François Ghiringhelli1–4,18, Lionel Apetoh1,2,5,6,18, Antoine Tesniere2,5,7,18, Laetitia Aymeric1,2,5,18, Yuting Ma1,2,5, Carla Ortiz1,2,5,8, Karim Vermaelen1,2,5,9, Theocharis Panaretakis2,5,7, Grégoire Mignot1–4, Evelyn Ullrich1,2,5, Jean-Luc Perfettini2,5,7, Frédéric Schlemmer2,5,7, Ezgi Tasdemir2,5,7, Martin Uhl10, Pierre Génin11, Ahmet Civas11, Bernhard Ryffel12, Jean Kanellopoulos13, Jürg Tschopp14, Fabrice André1,2,5, Rosette Lidereau15, Nicole M McLaughlin16, Nicole M Haynes16, Mark J Smyth16,18, Guido Kroemer2,5,7,18 & Laurence Zitvogel1,2,5,17,18 The therapeutic efficacy of anticancer chemotherapies may depend on dendritic cells (DCs), which present antigens from dying cancer cells to prime tumor-specific interferon- (IFN-)–producing T lymphocytes. Here we show that dying tumor cells release ATP, which then acts on P2X7 purinergic receptors from DCs and triggers the NOD-like receptor family, pyrin domain containing-3 protein (NLRP3)-dependent caspase-1 activation complex (‘inflammasome’), allowing for the secretion of interleukin-1 (IL-1). The priming of IFN-–producing CD8+ T cells by dying tumor cells fails in the absence of a functional IL-1 receptor 1 and in Nlpr3-deficient (Nlrp3–/–) or caspase-1–deficient (Casp-1–/–) mice unless exogenous IL-1 is provided. Accordingly, anticancer chemotherapy turned out to be inefficient against tumors established in purinergic receptor P2rx7–/–or Nlrp3–/–or Casp1–/–hosts. Anthracycline-treated individuals with breast cancer carrying a loss-of-function allele of P2RX7 developed metastatic disease more rapidly than individuals bearing the normal allele. These results indicate that the NLRP3 inflammasome links the innate and adaptive immune responses against dying tumor cells. It has been an ongoing conundrum to find which particular biochemical of co-stimulatory signals and cytokines that allow for the differentiation or metabolic alterations could be used to distinguish between of specific T cells12. One of the peculiarities of immunogenic cell 1,2 © All rights reserved. 2009 Inc. Nature America, immunogenic and nonimmunogenic cell death . Physiological cell death is early, preapoptotic exposure of calreticulin on the plasma death, which occurs as a continuous byproduct of cellular turnover, membrane, which facilitates the uptake of dying cells by DCs13. A is nonimmunogenic (or even tolerogenic). Avoidance of autoimmu- second characteristic of immunogenic cell death is the release of high nity likewise results from the fact that physiological cell death fails mobility group box-1 (HMGB1) protein from the nucleus into the to activate pattern recognition receptors, including Toll-like recep- surroundings of dying cells14. HMGB1 acts on TLR4 on DCs, and this tors (TLRs) and NOD-like receptors (NLRs) that recognize patho- interaction stimulates the processing of tumor antigens from dying gen and/or damage molecular patterns and activate innate immune cells15. However, addition of recombinant calreticulin or HMGB1 effectors3–9. In contrast, cell death elicited by radiotherapy and some to live cancer cells is not sufficient to elicit the presentation of tumor chemotherapeutic agents such as anthracyclines and oxaliplatin elicits antigens by DCs16, implying that additional, yet-to-be-identified an immune response required for the therapeutic success10,11. signals must be exchanged between dying cells and DCs. To mount a T cell immune response, DCs must incorporate anti- In macrophages, the so-called inflammasome serves as a central sen- gens from stressed or dying cells, acquire the competence of antigen sor for pathogen and/or damage molecular patterns17–19. In response processing in a maturation step and present antigenic peptides bound to danger signals, NLRP3 (also called NALP3 or cryopyrin) interacts to major histocompatibility complex (MHC) molecules in the context with the adaptor molecule apoptosis-associated speck-like protein 1Institut National de la Santé et de la Recherche Médicale (INSERM), U805, Villejuif, France. 2Institut Gustave Roussy, Villejuif, France. 3AVENIR team INSERM CRI-866, Dijon, France. 4Centre Georges Francois Leclerc, Dijon, France. 5Université Paris-Sud, Villejuif, France. 6Center for Neurological Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA. 7INSERM, U848, Villejuif, France. 8Universidad de Chile, Facultad de Ciencias Químicas Farmacéuticas, Centro FONDAP Estudios Moleculares de la Célula, Santiago, Chile. 9Laboratory of Immunoregulation, Department of Respiratory Medicine, Ghent University Hospital, Belgium. 10INSERM, U818, Institut Pasteur, Paris, France. 11UPR 2228-CNRS, Laboratoire de Régulation Transcriptionnelle et Maladies Génétiques, Biomédicale des Saints-Pères, Université Paris Descartes, Paris Cedex 06, France. 12UMR6218, IEM, CNRS Transgenose Institute, Orleans, France. 13UMR8619, CNRS, Université Paris, Orsay, France. 14Department of Biochemistry, University of Lausanne, Epalinges, Switzerland. 15Centre René Huguenin, INSERM U735, St. Cloud, France. 16Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. 17CICBT507, Villejuif, France. 18These authors contributed equally to this work. Correspondence should be addressed to L.Z. ([email protected]) or G.K. ([email protected]). Received 16 July; accepted 18 August; published online 20 september 2009; doi:10.1038/nm.2028 1170 VOLUME 15 | NUMBER 10 | OCTOBER 2009 NATURE MEDICINE A RTICLES Figure 1 The tumoricidal activity of oxaliplatin a 400 b 400 * depends on the NLRP3 inflammasome. ) * 2 WT PBS * m 300 300 (a–f) EL4 or EG7 thymoma tumor size in syngeneic WT WT PBS * –/– * WT e (m e Rag2 mice bearing the indicated genotypes (a–f) or –/– 200 * nu/nu Ox 200 Ifngr1 Ox injected with CD8-specific antibody (Anti-CD8 –/– Anti-CD8 Ab Il12r b2 or siz or Ab) and treated with oxaliplatin (Ox) (a). Each m 100 100 treatment group included five or six mice (data Tu 0 0 are means ± s.e.m.), and each experiment was 0 5 10 15 20 0 5 10 15 20 repeated at least twice with similar results. EL4 EL4 *P < 0.05. PBS-treated controls are only shown c d 500 * for tumors growing on WT mice. For PBS-treated 200 ) 2 400 * controls in all genotypes, see Supplementary m * * * Figure 1. Pfr1, gene encoding perforin. WT PBS 300 e (m e * 100 * WT WT PBS (g,h) IFN-γ secretion by inguinal lymph node 200 * Ifng–/– WT or siz or Ox –/– cells draining established EG7 tumors treated or –/– Pfr1 Ox m Ifngr 100 not with oxaliplatin (Ox) and re-stimulated with Tu OVA, as measured by ELISA (g). Monitoring by 0 0 0 5 10 15 20 0 5 10 15 20 immunofluorescence detection of intracellular EG7 EL4 IFN-γ of the proportion of IFN-γ–positive e f 400 + ) 200 CD8 T cells in inguinal lymph nodes draining 2 * * * m established EL4 or EG7 treated or not with Ox * WT PBS 300 * e (m e * WT after ex vivo re-stimulation with antibody to –/– * WT PBS 100 * Tnfsf10 200 CD3ε ± SIINFEKL peptides (h). Results (means –/– Ox WT or siz or Tnfsf10 P2rx7 –/– m –/– –/– Ox of triplicates ± s.e.m., n = 3 per group) are Pfr1 × Ifng 100 Nlrp3 –/– Tu representative of one typical experiment out of Casp1 –/– three. *P < 0.01. 0 0 0 5 10 15 20 0 5 10 15 20 EG7 EL4 Time (d) after treatment Anti-CD3 Ab (ASC, encoded by the Pycard gene) to form the g h Anti-CD3 Ab + SIINFEKL inflammasome, the principal Casp-1 activation 0.7% 0.8% 20–22 WT versus Casp1–/– EL4 ±0.3% ±0.3% complex . Casp-1 activated by the NLRP3 Ox PBS inflammasome is required for the proteolytic In vitro versus PBS re-stimulation OVA maturation of pro–IL-1 and hence IL-1 secre- oxaliplatin Day 5 β β 3.1% 2.6% γ tion in response to purinergic P2RX receptor - ±0.9% ±1.1% 7 1.2 EG7 agonists and TLR4 ligands23–26. Multiple * IFN 1.0 distinct bacterial products or endogenous ) –1 0.6% 13.0% damage signals stimulate the NLRP3 inflamma- l 0.8 m EG7 ±0.3% ±2.5% some, resulting in the proteolytic activation of 0.6 Ox Intracellular (ng (ng γ 25,27–30 - caspase-1 . Gain-of-function mutations 0.4 IFN 0.5% in NLRP3 that increase IL-1β secretion account EG7 2.0% 0.2 ±0.2% ±0.2% © All rights reserved. 2009 Inc. Nature America, for hereditary inflammatory diseases31,32. Ox 0 + IL-1RA Here we report the unexpected finding that Co PBS Ox Co PBS Ox the activation of the NLRP3 inflammasome WT Casp1–/– CD8 within DCs is decisive for the immune response against dying tumor cells, providing a previously unknown link between the innate and acquired immune systems. efficacy of chemotherapy for mouse CT26 colon cancers and mouse MCA2 sarcomas treated with doxorubicin (Supplementary Fig. 2 and RESULTS Supplementary Methods). Chemotherapy efficacy relies on the NLRP3 inflammasome In addition, tumors implanted in mice that lack either of two Oxaliplatin is efficient in controlling tumor growth in immuno- components of the inflammasome28, NLRP3 or Casp-1, failed to competent wild-type (WT) mice but loses its therapeutic efficacy on respond to oxaliplatin (Fig. 1f). Systemic oxaliplatin treatment primed syngeneic EL4 thymomas in Rag2–/– mice, which lack T and B cells, in T cells from the tumor-draining lymph node for IFN-γ production, and nu/nu mice, which lack T cells, in mice that have been depleted of CD8+ this chemotherapy-induced T cell priming was deficient in Casp1–/– T cells by injection of a specific antibody (Fig. 1a; for treated controls, mice (Fig. 1g). Intracellular staining revealed that dying tumor cells see Supplementary Fig. 1 and Supplementary Methods), and in mice primed CD8+ T cells for IFN-γ production and that an IL-1 recep- deficient in IFN-γ receptor-1 (Ifngr1–/– mice), yet remains efficient tor antagonist (IL-1RA33) applied with the chemotherapy abolished in mice deficient in IL-12 receptor-β2 (Il12rb2–/– mice) (Fig.
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