Control of regulatory T cells by IL-17 in colorectal cancer

Project Summary/Abstract: IL-17 family cytokines promote inflammation that drives the development of colorectal neoplasia, which eventually lead to colorectal cancer (CRC). Thus far, the underlying mechanism has largely been attributed to IL-17’s role in myeloid cell recruitment. Whether IL-17 also signals to adaptive immune cells, in particular CD4+ regulatory T cells (Tregs), and whether this signaling plays a role in colorectal tumorigenesis, remains unknown. Our preliminary studies show that targeted ablation of IL-17 signaling on Treg cells increased colonic tumor development in mice, demonstrating a previously unknown protective role of IL-17 in CRC. We also found that IL-17 directly inhibits Treg accumulation in tumors. Further, IL-17 inhibits the expression of genes that facilitate Treg migration, proliferation, and immune suppressive function. Importantly, these effects are only observed in tumor-infiltrating Tregs, suggesting a site-specific inhibition of Tregs by IL-17. Consistent with this notion, only tumor-infiltrating Tregs express IL-17RC and RE – co-receptors for IL-17A, C, and F cytokines. Stimulation of Tregs with IL-6 and IL-1β, two cytokines that are abundant in the tumor environment, upregulates IL-17RE, suggesting that the tumor microenvironment renders Tregs susceptible to IL-17-mediated inhibition. On the other hand, we also found that IL-17 signals to tumor cells to downregulate the expression of CXCL9 and 10, which signal through their cognate receptor CXCR3 to attract CD8+ CTLs to the tumor. These preliminary findings support our hypothesis that IL-17 regulates colorectal tumor development through two opposing mechanisms: 1) IL-17 directly inhibits Tregs that would otherwise suppress cancer immunosurveillance; and 2) IL-17 inhibits the attraction of CD8+ CTLs into the tumor environment by downregulating CXCL9/10 production. Given the critical roles of both Tregs and Th17 cells in tumor development, along with the knowledge gap relating to the impact of IL-17 on Treg biology, we propose the following studies: 1) Delineate how IL-17 mediates direct inhibition of Tregs in colorectal tumors; 2) Elucidate the molecular mechanism(s) underlying IL-17-mediated inhibition of Tregs; and 3) Interrogate how IL-17 inhibits T cell attraction through the regulation of CXCL9/10, and test the importance of IL-17-Treg circuitry in colorectal tumor development and therapy. These investigations will provide new insights into the mechanisms by which IL-17 impacts colorectal tumorigenesis, as well as guide the invention and use of novel therapies for the treatment of CRC in humans. For example, based on a role for IL- 17 in inhibiting CD8+ CTL attraction to tumor, we may employ currently available IL-17A and IL-17RA antibodies as adjuvant agents for cancer immunotherapy. However, for tumors that are abundant with IL-17 and Tregs, neutralizing IL-17 may further enhance Treg’s immune suppression and worsen treatment outcome. Uncoupling IL-17-Treg interactions may also be important for the treatment of autoimmunity and bacterial infections, and will be explored in subsequent studies.