Chemotherapy-triggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growth

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.

Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer

“…64,65 Recently, gemcitabine and 5-FU were shown to activate the inflammasome pathway in MDSCs, leading to IL-1b production, which, in turn, induced IL-17 secretion by CD4 T-cells and blunted the anticancer efficacy of chemotherapy. 66 In another report, however, optimal anticancer responses during doxorubicin treatment have been shown to require the IL-17-producing gd T-cell population. 52 A dosedependent effect on the expansion or differentiation of CD4 Tcells producing IL-17A was also observed in naive and tumorbearing mice following treatment with CTX.…”

Fluorouracil and bevacizumab plus anakinra for patients with metastatic colorectal cancer refractory to standard therapies (IRAFU): a single-arm phase 2 study

“…In mice, 5-FU induces caspase-1 activation and IL-1β release and induces the generation Th17 cells, which is inhibited by anakinra. 9 We observed a significant activation of caspase-1 in monocytic Myeloid derived suppressor cells (mMDSC) and a significant increase of serum IL-1β…”

“…Indeed, Caspase-1 activation and IL-1β release has been observed 24 hours after the first 5-FU injection. We previously observed that 5-FU regimen or FOLFOX regimen 9,17 prompts the accumulation of Th17 in patients’ blood and reduces the number of mMDSC. Immunomonitoring underlines a decrease in the number of mMDSC and the inversion of granulocyte/lymphocyte ratio after therapy.…”

“…Importantly, IL-1β related inflammation is not only dependent on tumor cells because 5-FU promotes the release of IL-1β by mMDSC. 9 In addition, studies in mice have shown that Il-1β favor tumor growth via Th17 generation and production of IL-17A. IL-17A and Th17 were previously described as factors for poor prognosis in human with CRC.…”

“…IL-1β was also shown to induce the generation and expansion of T H 17 cells, which could promote tumor growth by favoring proangiogenesis and immunosuppression in a IL-17A dependent manner. 9 Based on this rational we suggested that inhibition of IL-1β could reverse resistance to 5-FU plus bevacizumab therapy in mCRC.…”