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Immunology

A downside of chemotherapy

Nature Reviews Cancer volume 13, page 5 (2013)Cite this article

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In addition to cytotoxic effects, chemotherapy has also been shown to have both positive and negative effects on antitumour immune responses. Bruchard et al. have shown that the chemotherapeutics gemcitabine and 5-fluorouracil activate the NOD-like receptor, pyrin-domain-containing 3 (NLRP3) inflammasome in myeloid-derived suppressor cells (MDSCs) to suppress antitumour immunity. Chemotherapy activated caspase 1 (CASP1) in MDSCs from tumour-bearing mice and cancer patients; this was dependent on NLRP3 and induced the secretion of interleukin-1β (IL-1β). This inflammasome activation in MDSCs was triggered by chemotherapy-induced lysosomal permeabilization and release of cathepsin B (which activates NLRP3). IL-1β did not affect the cytotoxicity of chemotherapy directly, but its release from MDSCs induced the secretion of IL-17 by pro-inflammatory CD4+ T cells, which limited the effects of chemotherapy in mice. Tumours established in mice lacking Nlrp3, Casp1 or Il17a, in wild-type mice treated with an IL-1 receptor antagonist, or in mice depleted for CD4 were more responsive to gemcitabine or 5-fluorouracil therapy, supporting the necessity of this pathway for the immunosuppressive effects of chemotherapy.Therefore, antagonists of this pathway might help to improve the efficacy of gemcitabine and 5-fluorouracil chemotherapy.

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ORIGINAL RESEARCH PAPER

  1. Bruchard, M. et al. Chemotherapy-triggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growth. Nature Med. 2 Dec 2012 (doi:10.1038/nm.2999)

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  1. Sarah Seton-Rogers
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Seton-Rogers, S. A downside of chemotherapy. Nat Rev Cancer 13, 5 (2013). https://doi.org/10.1038/nrc3441

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