Chromatin accessibility of ILC2 co-stimulated by GITR signaling under Activation condition [ATAC-Seq]

Innate-lymphoid cells (ILCs) are key regulators of tissue homeostasis/immunity but their anti-tumor roles are poorly defined. Here, we identify the GITR-ILC2-IL-9-eosinophil axis as a key driver of anti-tumor immunity. Specifically, GITR co-stimulation of ILC2s in the tumor microenvironment (TME) induces ATF3-dependent chromatin remodeling that causes the ILC2s to produce IL-9 but not canonical ILC2 cytokines (e.g. IL-5 and IL-13). ILC2-derived IL-9 then promotes eosinophil cytotoxicity, as indicated by their elevated cytotoxic granule-associated gene expression and tumoricidal activity. The IL-9-stimulated eosinophils thus effect tumor control. These events are facilitated by TME-induced expression of IL-9 receptor on eosinophils. TCGA-data analysis showed that IL-9-signature expression associated with favorable prognosis in patients with melanoma and lung adenocarcinoma. Our findings thus establish the GITR-ILC2-IL-9 axis as a pivotal pathway that integrates innate lymphoid and granulocyte responses and drives tumor immunity. This pathway may be a promising therapeutic target for enhancing eosinophil-mediated tumor suppression.