Senescent tumor-infiltrating regulatory T cells and its role in renal clear cell carcinoma 3963

Abstract Description Tumor-infiltrating regulatory T cells (TI-Tregs) orchestrate an immunosuppressive tumor microenvironment critical for cancer development. Our analysis of single-cell RNAseq dataset revealed senescence-associated markers, such as p16, SA-β-gal, and BCL-XL in Tregs infiltrating human clear cell renal cell carcinoma (ccRCC) samples. These senescent Treg subpopulations could further contribute to an immunosuppressive tumor microenvironment (TME), promoting RCC progression. We hypothesize that senescent TI-Tregs overexpressing BCL-XL exist in a distinct activation state that reinforces their suppressive function. Ex vivo treatment of RCC patient-derived tumor slices with BCL-XL degrading proteolysis targeting chimera (PROTAC) drugs effectively reduced BCL-XL expression in Tregs. Although there was no significant change in Treg number, we observed an enhanced anti-tumor immune response. Our study demonstrates that depletion of BCL-XL in Tregs using proteolysis-targeting chimeras (PROTACs) can modulate the RCC TME in human RCC tissue. We conclude that PROTAC-mediated targeting of senescent TI-Tregs is a promising therapeutic approach for enhancing anti-tumor immunity in RCC. Ongoing studies aim to functionally characterize senescent TI-Tregs using innovative tools such as p16tdTom transgenic mice and NIR-BG2 probe, a chemical senescence tracer. These approaches will help unravel the activation states and functional roles of this intriguing Treg subpopulation within the RCC TME. Funding Sources R01CA269661 NIH/NCI Zhang (Contact PD/PI, 20%); University of Florida Health Cancer Cancer; EPIG Grant: Pathology, Immunology and Laboratory Medicine Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)