journal contribution
posted on 2023-04-04, 01:06 authored by Pengfei Wu, Bo Geng, Qun Chen, Enyang Zhao, Jiang Liu, Chen Sun, Caijun Zha, Yong Shao, Bosen You, Wenfu Zhang, Lulu Li, Xiangqi Meng, Jinquan Cai, Xuedong Li Supplementary Tables and Figures: Table S1, Table S2, Table S3, Table S4, Table S5, Table S6, Figure S1, Figure S2, Figure S3, Figure S4, Figure S5, Figure S6
Funding
The National Natural Science Foundation of China
The China Postdoctoral Science Foundation
The Research Project of the Chinese Society of Neuro-oncology
The Heilongjiang Postdoctoral Science Foundation
The Research Project of the Health and Family Planning Commission of Heilongjiang Province
The Harbin Medical University Scientific Research Innovation Fund
History
ARTICLE ABSTRACT
Dysfunction in T-cell antitumor activity contributes to the tumorigenesis, 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 TGFβ1 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 TGFβ1 had prognostic significance in patients with ccRCC, and its expression was associated with PD-1 mRNA expression. CcRCC-derived TGFβ1 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 TGFβ1 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 TGFβ1 mediates immune evasion and has potential as a prognostic biomarker and therapeutic target in ccRCC.See related Spotlight on p. 1464
