Intratumoral early activated TCF1+ CD4 Th cells drive effector CD8 T cell responses in a novel sarcomatoid RCC model through anti-CTLA4 therapy 3951

Abstract Description Renal cell carcinoma (RCC) is a highly immune-infiltrated tumor with a typically low tumor burden. Recent studies have identified a stem-like TCF1+ CD4 T cell population within RCC, possessing the potential for proliferation and differentiation. To investigate immune dynamics in RCC, we developed a novel sarcomatoid RCC (sRCC) mouse model (VhlmutBap1delCdkn2a/bdel), characterized by a highly immune-infiltrated tumor microenvironment. In this model, treatment with a regulatory T cell (Treg) -depleting anti-CTLA4 antibody significantly reduced Treg abundance and increased activated T helper (Th) 1 cells. Interestingly, only responder mice exhibited a selective expansion of the TCF1+ CD4 Th cell population, while non-responders did not. Furthermore, we found that these intratumoral TCF1+ CD4 Th cells expressed high levels of IL-2, which, in turn, promoted effector CD8 T cells with enhanced cytotoxic activity, as evidenced by further increased granzyme B and perforin secretion. These findings highlight a novel mechanism of Treg-depleting anti-CTLA4 therapy, which mediates its effects by expanding a TCF1+ CD4 Th cell subset that orchestrates robust CD8 T cell responses. This discovery offers new insights into immune modulation in RCC and suggests a potential pathway to improve immunotherapeutic strategies. Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)