ILC2-driven innate immune checkpoint mechanism antagonizes NK cell anti-metastatic function in the lung. Transcriptomic of mouse lung NK-cells

Metastasis constitutes the primary cause of cancer-related deaths, with the lung being a commonly affected organ. Here we found that activation of lung-resident group 2 innate lymphoid cells (ILC2) orchestrated suppression of Natural Killer (NK) cell-mediated innate anti-tumor immunity, leading to increased lung metastases and mortality. Using multiple models of lung metastasis, we show that IL-33-dependent ILC2-activation in the lung is centrally involved 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, 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 ILC2 in promoting tumor metastasis via their capacity to suppress innate type-1 immunity.