The RNA binding protein Ybx1 promotes regulatory T cell immunosuppressive function 2403

Abstract Description Regulatory T cells (Tregs) are essential for limiting cancer promoting chronic inflammation, but also contribute to the immunosuppressive tumor microenvironment. The mechanism by which the activity of Tregs is regulated in cancer remains largely unclear. Through bulk and single cell RNA sequencing, we found that tumor-infiltrating Tregs exhibit a significant increase in RNA splicing events, coupled with the upregulation of multiple RNA binding proteins (RBPs) and a gain in Treg transcriptional programs related to their activation and immunosuppressive function. Among the RBPs, Ybx1 is upregulated in tumor-infiltrating Tregs and this upregulation is in part promoted by IL-17 signaling on Tregs. We demonstrate that Ybx1 phosphorylation at the S102 site is promoted by IL-2 and CD3/CD28 co-stimulation in Tregs. Functionally, the knockout (KO) of Ybx1 in mouse Tregs reduced their in vitro suppressive function towards CD8+ T cell proliferation. Adoptive transfer of Ybx1 KO Tregs in Treg null mice led to splenomegaly and lymphomegaly, supporting Ybx1’s role in promoting Treg suppressive function. Mechanistically, RNAseq of mouse Ybx1 KO Tregs demonstrated the downregulation of immunosuppressive Treg marker galectin-1 (Lgals1) and suppressive cytokine IL-10. Additionally, both mouse and human Ybx1 KO Tregs exhibited a downregulation of Galectin-1 by flow cytometry. These findings support a novel role of Ybx1 in promoting Treg suppressive function in colorectal cancer. Funding Sources NIH CA262430 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)