Tumor cell-derived TGFb1 attenuates antitumor immune activity of T cells via regulation of PD-1 mRNA

Abstract

Dysfunction in T-cell antitumor activity contributes to the tumor-igenesis, progression, and poor outcome of clear cell renal cell carcinoma (ccRCC), with this dysfunction resulting from high expression of programmed cell death-1 (PD-1) in T cells. However, the molecular mechanisms maintaining high PD-1 expression in T cells have not been fully investigated in ccRCC. Here, we describe a mechanism underlying the regulation of PD-1 at the mRNA level and demonstrated its impact on T-cell dysfunction. Transcriptomic analysis identified a correlation between TGFb1 and PD-1 mRNA levels in ccRCC samples. The mechanism underlying the regulation of PD-1 mRNA was then investigated in vitro and in vivo using syngeneic tumor models. We also observed that TGFb1 had prognostic significance in patients with ccRCC, and its expression was associated with PD-1 mRNA expression. CcRCC-derived TGFb1 activated P38 and induced the phosphorylation of Ser10 on H3, which recruited p65 to increase SRSF3 and SRSF5 expression in T cells. As a result, the half-life of PD-1 mRNA in T cells was prolonged. SRSF3 coordinated with NXF1 to induce PD-1 mRNA extranuclear transport in T cells. We then demonstrated that TGFb1 could induce SRSF3 expression to restrict the antitumor activity of T cells, which influenced immunotherapy outcomes in ccRCC mouse models. Our findings highlight that tumor-derived TGFb1 mediates immune evasion and has potential as a prognostic biomarker and therapeutic target in ccRCC.