Chemotherapy-triggered Cathepsin B Release in Myeloid-Derived Suppressor Cells Activates the Nlrp3 Inflammasome and Promotes Tumor Growth

Nat Med. 2013 Jan;19(1):57-64. doi: 10.1038/nm.2999. Epub 2012 Dec 2.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • CD4-Positive T-Lymphocytes / metabolism
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Caspase 1 / genetics
  • Caspase 1 / metabolism*
  • Cathepsin B / genetics
  • Cathepsin B / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • Dendritic Cells / metabolism
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / pharmacology
  • Female
  • Fluorouracil / pharmacology*
  • Humans
  • Inflammasomes / metabolism*
  • Interleukin-17 / metabolism
  • Interleukin-1beta / biosynthesis
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • RNA Interference
  • RNA, Small Interfering
  • Receptors, Interleukin-1 / antagonists & inhibitors
  • Signal Transduction / immunology
  • bcl-2-Associated X Protein / genetics

Substances

  • Antineoplastic Agents
  • Carrier Proteins
  • Inflammasomes
  • Interleukin-17
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • RNA, Small Interfering
  • Receptors, Interleukin-1
  • bcl-2-Associated X Protein
  • Deoxycytidine
  • gemcitabine
  • Cathepsin B
  • Ctsb protein, mouse
  • Caspase 1
  • Fluorouracil