47TCF1+ CD4+ T cells mediate response to anti-CTLA-4 therapy in a sarcomatoid RCC mouse model

Abstract Background Dual immune checkpoint blockade (IO/IO) has significantly improved overall survival in renal cell carcinoma (RCC), but only ∼50% of patients initially respond to treatment. Understanding the mechanisms underlying primary response and resistance is critical to improving therapeutic outcomes. Methods We developed a novel mouse model of sarcomatoid RCC (sRCC) by targeting Vhl, Bap1, and Cdkn2a/b, recapitulating the genomic and histological features and tumor microenvironment of human sRCC. Mice were treated with anti-CTLA-4 antibody. Tumor-­infiltrating immune populations were analyzed using single-cell RNA sequencing and flow cytometry to evaluate T cell subsets and cytotoxic function. Results Anti-CTLA-4 treatment led to Treg depletion and an increase in activated Th1 cells. Importantly, only responder mice exhibited a selective expansion of TCF1+ CD4+ T cells. This was accompanied by increased granzyme B and perforin expression in effector CD8+ T cells, indicating enhanced cytotoxic activity. In contrast, non-responder mice lacked this TCF1+ CD4+ population and associated cytotoxic CD8+ responses. Conclusions Our findings reveal that Treg-depleting anti-CTLA-4 therapy promotes anti-tumor immunity by expanding a TCF1+ CD4+ T cell population that orchestrates CD8+ T cell responses. This mechanism offers a novel insight into immune modulation in sRCC and identifies a potential target to improve immunotherapy efficacy in RCC patients.