IL-17A as a Key Regulator of Regulatory T Cell Induction and Function by modulating PD-L1 Checkpoint in Colorectal Cancer

The balance between Th17 cells and regulatory T cells (Tregs) plays a vital role in maintaining host homeostasis. IL-17A, the hallmark cytokine of Th17 cells, has been implicated in cancers and autoimmune diseases. Interestingly, our previous research has revealed an unexpected negative feedback role of IL-17A to limit the pathogenicity of Th17 cells by inducing the immunosuppressive cytokine, IL-241. In this study, we delved into the role of IL-17A in modulating Tregs. In-vitro studies showed that IL-17A not only enhances the differentiation of Tregs but also boosts their suppressive capabilities. Mechanistic studies revealed that IL-17A significantly induces the expression of PD-L1 in Tregs via NF-kb signaling. To explore the in vivo impact, we employed the CD4creIL17RAflx mouse and the absence of IL17 receptor in CD4+ T cells hinders the progression of colorectal cancer (CRC) xenograft models by reducing the number of Tregs within the tumor microenvironment. Additionally, the expression of PD-L1 on these Tregs was significantly reduced, while there was an increased expression of IFN-γ from both tumor infiltrating CD4+ and CD8+ T cells. In conclusion, our findings indicate that IL-17A is crucial in promoting Tregs in the tumor microenvironment, at least in part by enhancing their expression of PD-L1. This suggests that IL-17A contributes to the immunosuppressive environment that allows CRC to progress. Reference: Chong WP, et. al., Immunity. 2020;53:384-397.e5.