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

Abstract

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. Single-cell and bulk transcriptomic analysis of lung NK cells reveals that post-transcriptional regulation likely accounts for IL-33-ILC2 dependent suppression of NK cell function. Using mass-spectrometry imaging (MSI) of the lungs of 13 C-Glucose infused mice, and metabolite profiling of ex vivo lung cultures, we find that IL-33 drives localized depletion of glucose via ILC2-dependent recruitment of highly glycolytic eosinophils, which can directly suppress lung NK cell function. 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.