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An innate IL-25-ILC2-MDSC axis creates a cancer-permissive microenvironment for Apc-mutation-driven intestinal tumorigenesis

ABSTRACT: Interleukin-25 and group 2 innate lymphoid cells (ILC2s) defend the host against intestinal helminth infection, and are associated with inappropriate allergic reactions. Recently, it was reported that IL-33-activated ILC2s augment protective tissue-specific pancreatic cancer immunity. Here we show a diametrically opposite role for intestinal IL-25-activated ILC2s where they create an innate cancer-permissive microenvironment. Colorectal cancer (CRC) patients with higher tumor IL25 expression have reduced survival, and increased IL-25 Rexpressing tumor-resident ILC2s and myeloid-derived suppressor cells (MDSCs) associated with impaired anti-tumor responses. Ablation of IL-25-signalling reduced tumors, virtually doubling life-expectancy in an Apc-mutation-driven model of spontaneous intestinal tumorigenesis. Mechanistically, IL-25 promotes tumor ILC2s, which sustain MDSCs to suppress anti-tumor immunity. Therapeutic blockade of IL-25-signalling decreased ILC2s, MDSCs and adenoma/adenocarcinoma, while increasing anti-tumor IFNg and adaptive T cell immunity. Thus, the roles of innate epithelium-derived cytokines IL-25 and IL-33, and ILC2s in cancer cannot be generalized, and instead offer differential pathways for therapeutic intervention.

ORGANISM(S): Mus musculus

PROVIDER: GSE199113 | GEO | 2022/04/20

REPOSITORIES: GEO

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Specification of innate type-2 lymphocytes by the transcriptional determinant Gfi1

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