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Chemotherapy-triggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growth

Abstract

Chemotherapeutic agents are widely used for cancer treatment. In addition to their direct cytotoxic effects, these agents harness the host's immune system, which contributes to their antitumor activity. Here we show that two clinically used chemotherapeutic agents, gemcitabine (Gem) and 5-fluorouracil (5FU), activate the NOD-like receptor family, pyrin domain containing-3 protein (Nlrp3)-dependent caspase-1 activation complex (termed the inflammasome) in myeloid-derived suppressor cells (MDSCs), leading to production of interleukin-1β (IL-1β), which curtails anticancer immunity. Chemotherapy-triggered IL-1β secretion relied on lysosomal permeabilization and the release of cathepsin B, which bound to Nlrp3 and drove caspase-1 activation. MDSC-derived IL-1β induced secretion of IL-17 by CD4+ T cells, which blunted the anticancer efficacy of the chemotherapy. Accordingly, Gem and 5FU exerted higher antitumor effects when tumors were established in Nlrp3−/− or Casp1−/− mice or wild-type mice treated with interleukin-1 receptor antagonist (IL-1Ra). Altogether, these results identify how activation of the Nlrp3 inflammasome in MDSCs by 5FU and Gem limits the antitumor efficacy of these chemotherapeutic agents.

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Figure 1: 5FU and Gem activate caspase-1 in MDSCs.
Figure 2: 5FU and Gem promote the secretion of bioactive IL-1β in a NLRP3-dependent manner.
Figure 3: 5FU- and Gem-induced NLRP3 inflammasome activation results from cathepsin B release from lysosomes.
Figure 4: Nlrp3 binds to cathepsin B.
Figure 5: NLRP3-dependent IL-1β production restrains the antitumor effect of 5FU.
Figure 6: NLRP3-dependent IL-1β production enhances IL-17 production by CD4+ T cells that restrain the antitumor effect of 5FU.

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Acknowledgements

The authors of this work are supported by the Fondation pour la Recherche Médicale (FRM) (F.G.), the Association pour le Recherche Contre le Cancer (ARC) (F.G., G.M. and M.B.), the Ligue Nationale Contre le Cancer (F.V.), the Institut National du Cancer (INCa) (F.G.), the Ligue Régionale Contre le Cancer Comité Grand-Est (F.G., C.R. and L.A.), the Fondation de France (F.G.), the Agence Nationale de la Recherche (ANR, ANR-10-PDOC-014-01) (L.A.), the European Commission (Marie Curie Fellowship PCIG10-GA-2011-303719) (L.A.), the Ministère de l'Enseignement Supérieur et de la Recherche (M.B.), INSERM and Région Bourgogne (F.C.) and LabEx ANR-11-LABX-0021. We thank P. Schneider (Biochemistry Department, Université de Lausanne), V. Bronte (Istituto Oncologico, Padova, Italy) and T. Reinheckel (Institute of Molecular Medicine and Cell Research Freiburg, Germany) for providing essential material.

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M.B., G.M., V.D., F.C., A.C., F.V., W.B., B.S. and C.R. performed in vitro experiments. M.B. and L.A. performed in vivo experiments. B.R., J.L.C. and J.K. provided essential materials. M.B., G.M., L.A., F.M. and F.G. designed the study and analyzed results. M.B., L.A. and F.G. wrote the paper.

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Correspondence to François Ghiringhelli.

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Bruchard, M., Mignot, G., Derangère, V. et al. Chemotherapy-triggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growth. Nat Med 19, 57–64 (2013). https://doi.org/10.1038/nm.2999

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