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Activation of the NLRP3 inflammasome in dendritic cells induces IL-1β–dependent adaptive immunity against tumors

Nature Medicine volume 15, pages 1170–1178 (2009)Cite this article

Abstract

The therapeutic efficacy of anticancer chemotherapies may depend on dendritic cells (DCs), which present antigens from dying cancer cells to prime tumor-specific interferon-γ (IFN-γ)–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-1β (IL-1β). The priming of IFN-γ–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-1β 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.

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Figure 1: The tumoricidal activity of oxaliplatin depends on the NLRP3 inflammasome.
Figure 2: ATP release by dying tumor cells dictates the immunogenicity of cell death.
Figure 3: Purinergic P2RX7 receptors are mandatory for the DC-mediated immunogenicity of cell death.
Figure 4: Activation of caspase-1 and IL-1β secretion in DCs exposed to dying tumor cells.
Figure 5: The NLRP3 inflammasome is required for the elicitation of an adaptive antitumor immune response.
Figure 6: NLRP3 inflammasome-dependent differentiation of tumor specific CD8+ T cells toward IFNγ polarization.

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Acknowledgements

We thank I. Couillin (CNRS) and A. Mignon (Cochin Hospital) for helpful discussion and for providing IL-1RA, R. Schreiber (Washington University School of Medicine) for monoclonal antibodies to IL-1α, IL-1β and IL-1R, H. Yang (Feinstein Institute for Medical Research) for antibody to HMGB1, H. Yagita (School of Medicine, Juntendo University) for the N2B2 antibody to mouse TRAIL, J.-C. Guéry (INSERM) for IL12rb2−/− mice, V. Dixit (Pennington Biomedical Research Center) for Pycard−/− mice, M. Albert (Pasteur Institute) for membrane-bound OVA–transfected mouse embryonic fibroblast cells, S. Forget and J. Bombled for access to the genomics platform, V. Vasseur and the Institut Gustave Roussy animal facility for breeding of transgenic mice, I. Martins for help in ATP release screening and A. Boissonnas (INSERM, Curie Institute) for providing OT1-GFP mice. We are deeply indebted to P. Arveux and S. Dabakuyo for useful help with the statistical analyses. The authors are supported by grants from the Ligue Nationale contre le Cancer (to L. Aymeric., G.K. and L.Z.), the Fondation pour la Recherche Médicale (to L. Apetoh., G.K., E.U., F.S. and L.Z.), the European Union (INFLACARE grant), the association for International cancer research (to G.K.) Cancéropôle Ile-de-France, Institut National du Cancer (L.Z., G.K.), Agence Nationale pour la Recherche (to G.K.), the European Molecular Biology Organization (L. Apetoh.), INSERM (A.T.), the National Health, Association pour la recherche sur le cancer RC (to G.M.), National Health and Medical Research Council of Australia, Cancer Council of Victoria, the China Scholarship Council (Y.M.) and the Leukemia Foundation (M.J.S., N.M.M. and N.M.H.). K.V. is the recipient of a European Respiratory Society Fellowship (number 605).

Author information

Author notes

  1. François Ghiringhelli, Lionel Apetoh, Antoine Tesniere, Laetitia Aymeric, Mark J Smyth, Guido Kroemer and Laurence Zitvogel: These authors contributed equally to this work.

Authors and Affiliations

  1. Institut National de la Santé et de la Recherche Médicale (INSERM), U805, Villejuif, France

    François Ghiringhelli, Lionel Apetoh, Laetitia Aymeric, Yuting Ma, Carla Ortiz, Karim Vermaelen, Grégoire Mignot, Evelyn Ullrich, Fabrice André & Laurence Zitvogel

  2. Institut Gustave Roussy, Villejuif, France

    François Ghiringhelli, Lionel Apetoh, Antoine Tesniere, Laetitia Aymeric, Yuting Ma, Carla Ortiz, Karim Vermaelen, Theocharis Panaretakis, Evelyn Ullrich, Jean-Luc Perfettini, Frédéric Schlemmer, Ezgi Tasdemir, Fabrice André, Guido Kroemer & Laurence Zitvogel

  3. AVENIR team INSERM CRI-866, Dijon, France

    François Ghiringhelli

  4. Centre Georges Francois Leclerc, Dijon, France

    François Ghiringhelli & Grégoire Mignot

  5. Université Paris-Sud, Villejuif, France

    Lionel Apetoh, Antoine Tesniere, Laetitia Aymeric, Yuting Ma, Carla Ortiz, Karim Vermaelen, Theocharis Panaretakis, Evelyn Ullrich, Jean-Luc Perfettini, Frédéric Schlemmer, Ezgi Tasdemir, Fabrice André, Guido Kroemer & Laurence Zitvogel

  6. Center for Neurological Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Lionel Apetoh

  7. INSERM, U848, Villejuif, France

    Antoine Tesniere, Theocharis Panaretakis, Jean-Luc Perfettini, Frédéric Schlemmer, Ezgi Tasdemir & Guido Kroemer

  8. Universidad de Chile, Facultad de Ciencias Químicas Farmacéuticas, Centro FONDAP Estudios Moleculares de la Célula, Santiago, Chile

    Carla Ortiz

  9. Department of Respiratory Medicine, Laboratory of Immunoregulation, Ghent University Hospital, Belgium

    Karim Vermaelen

  10. INSERM, U818, Institut Pasteur, Paris, France

    Martin Uhl

  11. UPR 2228-CNRS, Laboratoire de Régulation Transcriptionnelle et Maladies Génétiques, Biomédicale des Saints-Pères, Université Paris Descartes, Paris Cedex 06, France

    Pierre Génin & Ahmet Civas

  12. UMR6218, IEM, CNRS Transgenose Institute, Orleans, France

    Bernhard Ryffel

  13. UMR8619, CNRS, Université Paris, Orsay, France

    Jean Kanellopoulos

  14. Department of Biochemistry, University of Lausanne, Epalinges, Switzerland

    Jürg Tschopp

  15. Centre René Huguenin, INSERM U735, St. Cloud, France

    Rosette Lidereau

  16. Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia

    Nicole M McLaughlin, Nicole M Haynes & Mark J Smyth

  17. CICBT507, Villejuif, France

    Laurence Zitvogel

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  1. François Ghiringhelli
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Contributions

F.G., L. Aymeric., A.T., L. Apetoh., T.P., F.S., G.M., E.U., Y.M., N.M.M., N.M.H. and M.J.S. performed in vitro and in vivo experiments. C.O., E.T., P.G. and A.C. performed in vitro experiments. A.T. and T.P. performed immunofluorescence experiments. M.U., J.-L.P., B.R., J.K. and J.T. provided transgenic cells or mice and gave scientific advice. K.V., F.A., R.L., F.G. and A.T. performed the single nucleotide polymorphism analysis on cohorts of subjects with cancer. F.G., L. Apetoh., M.J.S. and A.T. prepared the figures and drafted the manuscript. G.K. and L.Z. designed the study and wrote the manuscript. M.J.S., G.K. and L.Z. all contributed equally to the design of the experiments and to the writing of the manuscript.

Corresponding authors

Correspondence to Guido Kroemer or Laurence Zitvogel.

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Ghiringhelli, F., Apetoh, L., Tesniere, A. et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1β–dependent adaptive immunity against tumors. Nat Med 15, 1170–1178 (2009). https://doi.org/10.1038/nm.2028

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