Abstract
Inflammasome activation in MDSCs induced by gemcitabine and 5-FU suppresses antitumor immunity.
Major finding: Inflammasome activation in MDSCs induced by gemcitabine and 5-FU suppresses antitumor immunity.
Mechanism: The NLRP3 inflammasome stimulates IL-1β release, which enhances IL-17 secretion by CD4+ T cells.
Impact: Inhibitors of IL-1β or the NLRP3 inflammasome may increase the efficacy of chemotherapeutic agents.
Chemotherapeutic agents exert cytotoxic effects on tumor cells but can also affect host immune responses. Some drugs, such as gemcitabine and 5-fluorouracil (5-FU), can selectively eliminate a population of immunosuppressive host cells known as myeloid-derived suppressor cells (MDSC), but their antitumor effects are limited. Bruchard and colleagues further characterized the effects of gemcitabine and 5-FU on MDSCs to gain insight into resistance mechanisms and found that both drugs induced lysosome permeabilization in the MDSCs of tumor-bearing mice, causing cathepsin B release. Cathepsin B bound and activated the NOD-like receptor family, pyrin domain containing-3 protein (NLRP3)-dependent caspase-1 activation complex (also known as the NLRP3 inflammasome), culminating in caspase-1 activation and production of interleukin (IL)-1β. Induction of this pathway leading to IL-1β secretion by MDSCs reduced the antitumor activity of the chemotherapeutic agents, as 5-FU was more effective in tumor-bearing Nrlp3- and Casp1-null mice as well as in wild-type mice treated with anakinra, an IL-1 receptor (IL-1R) antagonist approved for treatment of rheumatoid arthritis. The level of IL-1β produced by MDSCs in response to gemcitabine and 5-FU was sufficient to drive IL-17 production by inflammatory CD4+ T cells. CD4 depletion or genetic inactivation of IL-17 enhanced the antitumor effect of 5-FU in an IL-1R–dependent manner, indicating that MDSC-induced IL-17 production in CD4+ T cells serves to limit the efficacy of chemotherapeutic agents. Importantly, cathepsin B and caspase-1 induction were observed in circulating MDSCs and serum IL-1β levels were elevated in the majority of a group of patients with metastatic colorectal cancer treated with 5-FU, suggesting that these findings have clinical relevance and raising the possibility that agents already approved or in development for inflammatory disorders may increase the efficacy of chemotherapeutic agents.
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