ILC2-driven innate immune checkpoint mechanism antagonizes NK cell antimetastatic function in the lung.

Abstract:: Metastasis constitutes the primary cause of cancer-related deaths, with the lung being a commonly affected organ. We found that activation of lung-resident group 2 innate lymphoid cells (ILC2s) orchestrated suppression of natural killer (NK) cell-mediated innate antitumor immunity, leading to increased lung metastases and mortality. Using multiple models of lung metastasis, we show that interleukin (IL)-33-dependent ILC2 activation in the lung is involved centrally in promoting tumor burden. ILC2-driven innate type 2 inflammation is accompanied by profound local suppression of interferon-γ production and cytotoxic function of lung NK cells. ILC2-dependent suppression of NK cells is elaborated via an innate regulatory mechanism, which is reliant on IL-5-induced lung eosinophilia, ultimately limiting the metabolic fitness of NK cells. Therapeutic targeting of IL-33 or IL-5 reversed NK cell suppression and alleviated cancer burden. Thus, we reveal an important function of IL-33 and ILC2s in promoting tumor metastasis via their capacity to suppress innate type 1 immunity.

Authors:: MJ Schuijs, S Png, AC Richard, A Tsyben, G Hamm, J Stockis, C Garcia, S Pinaud, A Nicholls, XR Ros, J Su, MD Eldridge, A Riedel, EM Serrao, H-R Rodewald, M Mack, JD Shields, ES Cohen, ANJ McKenzie, RJA Goodwin, KM Brindle, JC Marioni, TYF Halim

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