期刊
NATURE MEDICINE
卷 19, 期 1, 页码 57-64出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.2999
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资金
- Fondation pour la Recherche Medicale (FRM)
- Association pour le Recherche Contre le Cancer (ARC)
- Ligue Nationale Contre le Cancer
- Institut National du Cancer (INCa)
- Ligue Regionale Contre le Cancer Comite Grand-Est
- Fondation de France
- Agence Nationale de la Recherche (ANR) [ANR-10-PDOC-014-01]
- European Commission (Marie Curie Fellowship) [PCIG10-GA-2011-303719]
- Ministere de l'Enseignement Superieur et de la Recherche
- INSERM
- Region Bourgogne
- LabEx [ANR-11-LABX-0021]
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-1 beta (IL-beta), which curtails anticancer immunity. Chemotherapy-triggered IL-1 beta secretion relied on lysosomal permeabilization and the release of cathepsin B, which bound to Nlrp3 and drove caspase-1 activation. MDSC-derived IL-1 beta 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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