Controlling tumor-infiltrating regulatory T cell function by the IL-17-Ybx1 signaling pathway
openNCI - National Cancer Institute
Project Summary/Abstract:
Regulatory T cells (Tregs) play key roles in immune homeostasis, tumor development, and cancer therapy
through suppression of inflammation. How the inflammatory tumor environment shapes the behavior of Tregs in
turn, is less known. This knowledge gap precludes our ability to selectively block the activity of tumor infiltrating
Tregs, while leaving systemic Treg function intact. One of the prominent inflammatory pathways involves
interleukin-17 (IL-17), which has been shown to promote tumor development in multiple tissues including the gut.
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 impact on tumor cells and myeloid cells. 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 found that IL-17 directly signals to Tregs to promote their immune suppressive
signature and more importantly, alternative splicing of RNAs in these cells. We also found that IL-17 promotes
the expression of the RNA binding protein (RBP), Ybx1, and enhances the splicing of RNAs whose protein
products are critical for Treg function. These genes (Foxp3, IL-27RA, and Stat3) also contain RNA motifs that
can be recognized by Ybx1, whose role in Treg is unknown. Ablation of Ybx1 in both human and mouse Tregs
resulted in reduced Treg immune suppression function, and reduced expression of immune suppressive protein
Galactin-1. We demonstrate that proper splicing of Galactin-1 mRNA depends on Ybx1. These findings lead to
our hypothesis that IL-17 promotes Treg function and suppresses CRC development through Ybx1
mediated alternative RNA splicing, and that a similar IL-17-Ybx1 pathway promotes Treg activity in
established tumors and impedes cancer immunotherapy. Given the critical roles of both Tregs and Th17
cells in tumor development and cancer therapy, along with the knowledge gap relating to the impact of RBPs on
Treg biology, we propose the following studies: 1) delineate the mechanism by which the IL-17-Ybx1 pathway
regulates alternative RNA splicing and function of Tregs; 2) test if the IL-17-Ybx1 pathway in CRC can be
manipulated to prevent gut tumorigenesis; and 3) test the feasibility of targeting IL-17-Ybx1 pathway for the
enhancement of cancer immunotherapy. These investigations will provide new insights into the mechanisms by
which the inflammatory tumor microenvironment (TME) controls Treg function, and guide the invention and use
of novel therapies for the treatment of CRC in humans. For example, based on a role for Ybx1 in promoting
immune suppressive function of Tregs in CRC, we may employ targeted therapy by degrading Ybx1 in tumor
infiltrating Tregs to foster an immunologically “hot” environment for enhanced cancer immunotherapy.
Justification for the use of animal models
We propose to use multiple animal models of cancers in this project. These models closely mimic human
colorectal cancers by simulating tumor cell mutation process, microbiota interaction, and tumor environment
evolution, allowing us to interrogate the mechanism of Ybx1-controlled Treg cell function in cancers. These
models cannot be replaced with non-animal studies such as in vitro cell culture or organs-on-a-chip systems.
Up to $485K
health research