FOXP1-mediated regulation of CD8 T cell stemness and immunity: Overcoming T cell exhaustion in chronic viral infections and cancer 3004

Abstract Description Chronic viral infections and cancer drive T cells into exhaustion, impairing their ability to eliminate infected or malignant cells. Exhaustion hinders effective immunotherapy and lasting immunity, highlighting the need for new targets to reduce T cell exhaustion and strengthen immune responses. Using scATAC-seq+ RNA-seq analyses, we identified FOXP1 as a key regulator of T cell stemness, crucial for maintaining persistent immunity by supporting the self-renewal and replenishment of exhausted T cells. FOXP1 overexpression enhances the expansion and differentiation of stem-like (SL) antiviral CD8 T cells and CAR CD8 T cells, significantly boosting antiviral and antitumor responses. In antiviral CD8 T cells, FOXP1 upregulates genes such as Ccr7, IL7r, and Sell, which are associated with T cell stemness. In CD8+ CAR-T cells, FOXP1 also preserves stemness by limiting differentiation from the SL subset to effector-like cells through transcriptional and epigenetic programming. Additionally, increasing expression of FOXP1 improves expansion and persistence of antiviral CD8 T cells. We further defined the function of each domain in FOXP1 in regulating differentiation and immune response of T cells. Our results suggest that harnessing FOXP1 may represent a novel immunotherapy strategy to improve T cell immunity against chronic infections and cancer. Funding Sources Supported by NIH/ NIA AG-083398; NIAID AI-158294, NIAID AI-158294 Diversity Supplement Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)