Chemotherapy-triggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growth.
Fiche publication
Date publication
janvier 2013
Journal
Nature medicine
Auteurs
Membres identifiés du Cancéropôle Est :
Dr BOIREAU Wilfrid, Pr GHIRINGHELLI François, Dr VEGRAN Frédérique, Dr REBE Cédric, Dr BRUCHARD Mélanie, Dr CHALMIN Fanny, Dr DERANGERE Valentin
Tous les auteurs :
Bruchard M, Mignot G, Derangère V, Chalmin F, Chevriaux A, Végran F, Boireau W, Simon B, Ryffel B, Connat JL, Kanellopoulos J, Martin F, Rébé C, Apetoh L, Ghiringhelli F
Lien Pubmed
Résumé
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.
Mots clés
Animals, Antineoplastic Agents, pharmacology, CD4-Positive T-Lymphocytes, metabolism, Carrier Proteins, genetics, Caspase 1, genetics, Cathepsin B, genetics, Cell Line, Tumor, Cell Proliferation, Dendritic Cells, metabolism, Deoxycytidine, analogs & derivatives, Female, Fluorouracil, pharmacology, Humans, Inflammasomes, metabolism, Interleukin-17, secretion, Interleukin-1beta, biosynthesis, Macrophages, metabolism, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, NLR Family, Pyrin Domain-Containing 3 Protein, Neoplasms, genetics, RNA Interference, RNA, Small Interfering, Receptors, Interleukin-1, antagonists & inhibitors, Signal Transduction, immunology, bcl-2-Associated X Protein, genetics
Référence
Nat. Med.. 2013 Jan;19(1):57-64