| Chemotherapy-triggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growth. | |
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MedLine Citation:
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PMID: 23202296 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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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Authors:
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Mélanie Bruchard; Grégoire Mignot; Valentin Derangère; Fanny Chalmin; Angélique Chevriaux; Frédérique Végran; Wilfrid Boireau; Benoit Simon; Bernhard Ryffel; Jean Louis Connat; Jean Kanellopoulos; François Martin; Cédric Rébé; Lionel Apetoh; François Ghiringhelli |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-12-02 |
Journal Detail:
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Title: Nature medicine Volume: - ISSN: 1546-170X ISO Abbreviation: Nat. Med. Publication Date: 2012 Dec |
Date Detail:
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Created Date: 2012-12-3 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9502015 Medline TA: Nat Med Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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1] Institut National de la Santé et de la Recherche Médicale (INSERM) U866, Dijon, France. [2] Faculté de Médecine et pharmacie, Université de Bourgogne, Dijon, France. [3]. |
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