Chemotherapeutics Inflame Tumor Growth

Science Signaling  15 Jan 2013:
Vol. 6, Issue 258, pp. ec12
DOI: 10.1126/scisignal.2003959

Whereas acute inflammation induced by chemotherapeutics aids in the antitumor response, chronic inflammation is protumorigenic. Gemcitabine (Gem) and 5-fluorouracil (5-FU) disrupt DNA replication to inhibit rapidly dividing cells, which can disrupt tumor growth and also enhance the activation of tumor-specific CD8+ T cells by selectively depleting myeloid-derived suppressor cells (MDSCs), but these drugs do not prevent tumor relapse. Bruchard et al. showed that Gem and 5-FU stimulated the release of protumorigenic interleukins from MDSCs before their depletion and that this was a mechanism that limited their antitumor efficacy. In MSC-2 cells, established cultures of MDSCs, Gem, or 5-FU activated the NOD-like receptor family pyrin domain–containing-3 protein (NLRP3)–dependent “inflammasome” complex—which activates caspase-1 to stimulate interleukin-1β (IL-1β) secretion—by inducing a cytosolic influx of cathepsin B, which is normally contained in lysosomes. Addition of a cathepsin B inhibitor or bafilomycin A, a lysosomal acidification inhibitor, to MSC-2 cells reduced 5-FU- or Gem-induced caspase-1 activation. In tumor-bearing mice and colon cancer patients treated with either Gem or 5-FU, NLRP3 activation and IL-1β secretion occurred exclusively with MDSCs. Genetic inactivation of either NLRP3 or caspase-1 to prevent IL-1β secretion restricted tumor growth and prolonged survival of 5-FU–treated mice bearing EL4 (lymphoblast), 4T1 (mammary), B16F10 (melanoma), or LLC (Lewis lung) carcinomas. Similarly, genetic inactivation of the IL-1 receptor (IL-1R) or treatment with an IL-1R antagonist (IL-1Ra) also enhanced the antiproliferative effect of 5-FU on EL4 tumor cells but did not affect tumor cell viability, indicating that the effects of IL-1β were on mouse host, not the xenografted tumor cells. MDSC-secreted IL-1β enhanced the secretion of a second cytokine, IL-17, from proinflammatory CD4+ T cells, the population of which increased in the tumor-draining lymph nodes of mice treated with 5-FU or Gem. IL-17 is implicated in angiogenesis, a critical process for tumor progression. The expression of proangiogenic genes (Eng and Pecam1) and T helper 17 cell–related genes (Il17a and Rorc), which are all regulated by IL-17, in the tissue surrounding the tumor was increased in vivo. IL-1Ra treatment combined with 5-FU blocked the induction of IL-17–regulated genes. Similar to Nlrp3–/– or Il-1R–/– cells, 5-FU was more effective at restricting tumor growth in Il17a–/– than in wild-type mice. MDSC depletion was critical to the antitumor effect of 5-FU, but depletion with 5-FU alone was not achievable without caspase-1 activation. The findings indicate that an improved chemotherapeutic strategy may be to combine IL-1 inhibition and 5-FU treatment.

M. Bruchard, G. Mignot, V. Derangère, F. Chalmin, A. Chevriaux, F. Végran, W. Boireau, B. Simon, B. Ryffel, J. L. Connat, J. Kanellopoulos, F. Martin, C. Rébé, L. Apetoh, F. Ghiringhelli, Chemotherapy-triggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growth. Nat. Med. 19, 57–64 (2013). [PubMed]