ILC2-driven innate immune checkpoint mechanism antagonizes NK cell antimetastatic function in the lung.
(2020) Nature immunology — Vol. 21, n° 9, p. 998-1009 (2020)
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Png, Shaun 
Richard, Arianne C
- 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.
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Citations
Schuijs, M. J., Png, S., Richard, A. C., Tsyben, A., Hamm, G., Stockis, J., Garcia, C., Pinaud, S., Nicholls, A., Ros, X. R., Eldridge, M. D., Riedel, A., Serrao, E. M., Rodewald, H.-R., Mack, M., Shields, J. D., Cohen, E. S., McKenzie, A. N. J., Goodwin, R. J. A., et al. (2020). ILC2-driven innate immune checkpoint mechanism antagonizes NK cell antimetastatic function in the lung. Nature immunology, 21(9), 998-1009. https://doi.org/10.1038/s41590-020-0745-y (Original work published 2020)