Editors' ChoiceCancer

Unconventional interleukin-1β release suppresses antitumor immunity

See allHide authors and affiliations

Science Translational Medicine  20 Jan 2021:
Vol. 13, Issue 577, eabg4726
DOI: 10.1126/scitranslmed.abg4726

Abstract

Inflammasome-independent release of IL-1β in the tumor microenvironment recruits T cell–suppressive neutrophils that support cancer progression.

Interleukin-1 β (IL-1β) is a key driver of inflammation in different autoimmune and chronic inflammatory diseases. This is exemplified by the CANTOS trial that reported reduced recurrent cardiovascular events in patients that received anti–IL-1β antibodies. Anti–IL-1β antibody therapy also showed reduced lung cancer incidence in those patients, highlighting an important role for IL-1β in driving cancer progression. Thus, inhibiting tumor-associated inflammation appears to improve disease outcome, but the underlying mechanisms are incompletely understood.

Kiss et al. aimed to unravel which cells in the tumor microenvironment (TME) produce IL-1β, how they release it, and how this affects tumor growth. They started by exploring single-cell transcriptomics data from non-small cell lung cancer and breast cancer patients and found that myeloid cell subsets expressed the highest levels of IL1B in both tumor types. Next, they turned to subcutaneous Lewis lung carcinoma (LLC) and orthotopic E0771 breast cancer mouse models to study the mechanisms by which IL-1β affects tumor progression in detail. IL-1β deficiency delayed tumor growth and reduced the expansion of circulating neutrophils and their infiltration into the tumor in both cancer models. IL-1β is produced as the inactive pro–IL-1β precursor that normally first needs to be cleaved by inflammasome-activated caspase-1 before being secreted via specific membrane pores. Strikingly, all of those, as well as caspase-8 and -11, were superfluous for the release of active IL-1β and subsequent recruitment of neutrophils into tumors. Mechanistically, tumor-infiltrating neutrophils were next shown to suppress T cell proliferation via nitric oxide. Accordingly, the impaired recruitment of immunosuppressive neutrophils in IL-1β–deficient mice was accompanied by elevated levels of cytotoxic CD8+ T cells, and these effector cells were required for the inhibition of tumor growth. Tumor-associated macrophages (TAMs) played a pivotal role in this anti-tumor response, as they were required to activate CD8+ T cells in the absence of IL-1β.

An important open question to be addressed is how bioactive IL-1β is produced and released in the TME. These data also warrant further investigations on the efficacy of therapeutic inflammasome inhibition in distinct cancer types. Moreover, TAM-reprogramming anti-tumor therapies aimed to elicit “M1-like” proinflammatory phenotypes should be performed with caution as they can up-regulate IL-1β and consequent immunosuppression.

Highlighted Article

Stay Connected to Science Translational Medicine

Navigate This Article