Document Detail

Chemotherapy-triggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growth.
MedLine Citation:
PMID:  23202296     Owner:  NLM     Status:  MEDLINE    
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.
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:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-12-02
Journal Detail:
Title:  Nature medicine     Volume:  19     ISSN:  1546-170X     ISO Abbreviation:  Nat. Med.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-08     Completed Date:  2013-03-06     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  9502015     Medline TA:  Nat Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  57-64     Citation Subset:  IM    
Institut National de Santé et de Recherche Médicale (INSERM) U866, Dijon, France.
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MeSH Terms
Antineoplastic Agents / pharmacology
CD4-Positive T-Lymphocytes / metabolism
Carrier Proteins / genetics,  metabolism*
Caspase 1 / genetics,  metabolism*
Cathepsin B / genetics,  metabolism
Cell Line, Tumor
Cell Proliferation
Dendritic Cells / metabolism
Deoxycytidine / analogs & derivatives*,  pharmacology
Fluorouracil / pharmacology*
Inflammasomes / metabolism*
Interleukin-17 / secretion
Interleukin-1beta / biosynthesis
Macrophages / metabolism
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Neoplasms / genetics,  metabolism*
RNA Interference
RNA, Small Interfering
Receptors, Interleukin-1 / antagonists & inhibitors
Signal Transduction / immunology
bcl-2-Associated X Protein / genetics
Reg. No./Substance:
0/Antineoplastic Agents; 0/CIAS1 protein, mouse; 0/Carrier Proteins; 0/Inflammasomes; 0/Interleukin-17; 0/Interleukin-1beta; 0/RNA, Small Interfering; 0/Receptors, Interleukin-1; 0/bcl-2-Associated X Protein; 51-21-8/Fluorouracil; 951-77-9/Deoxycytidine; B76N6SBZ8R/gemcitabine; EC B; EC protein, mouse; EC 1
Comment In:
Nat Med. 2013 Jan;19(1):20-2   [PMID:  23296003 ]

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