Interleukin-17 directly stimulates tumor infiltrating Tregs to prevent cancer development [scRNA-seq]

Interleukin-17 (IL-17) family cytokines promote protective inflammation for pathogen resistance, but also facilitate autoimmunity and tumor development. A direct signal of IL-17 to regulatory T cells (Tregs) has not been reported and may help explain these dichotomous responses. Here we show in mice that IL-17 Receptor A (IL-17RA) is expressed in Tregs that reside in mouse mesenteric lymph nodes and colon tumors, as well as in patients with colorectal cancer (CRC). Ablation of IL-17RA, specifically in Tregs, resulted in increased Th17 cells, and exacerbated tumor development. Mechanistically, tumor-infiltrating Tregs exhibit a unique gene signature that is linked to their activation, maturation, and suppression function, and this signature is in part supported by the direct signaling of IL-17 to Tregs. To study pathways of Treg programming, we found that loss of IL-17RA in tumor Tregs resulted in reduced RNA splicing, and downregulation of several RNA binding proteins that are known to regulate alternative splicing and promote Treg function. Taken together, we report a direct role of IL-17 in promoting Treg maturation and function in CRC. Overall design: Bone marrow cells from Foxp3-YFP-Cre+/Il17raF/F (KO) and Foxp3-YFP-Cre+/Il17raF/+ (WT control) mice were adoptively transferred into 6-8-week-old Cdx2-Cre+/ApcF/+ mice. Bone marrow recipient mice were then sacrificed at 5 months of age, and their mesenteric lymph nodes (MLN) and tumors were disected.