RT Journal Article
SR Electronic
T1 Tumor Cell–Derived TGFβ1 Attenuates Antitumor Immune Activity of T Cells via Regulation of PD-1 mRNA
JF Cancer Immunology Research
JO Cancer Immunol Res
FD American Association for Cancer Research
SP 1470
OP 1484
DO 10.1158/2326-6066.CIR-20-0113
VO 8
IS 12
A1 Wu, Pengfei
A1 Geng, Bo
A1 Chen, Qun
A1 Zhao, Enyang
A1 Liu, Jiang
A1 Sun, Chen
A1 Zha, Caijun
A1 Shao, Yong
A1 You, Bosen
A1 Zhang, Wenfu
A1 Li, Lulu
A1 Meng, Xiangqi
A1 Cai, Jinquan
A1 Li, Xuedong
YR 2020
UL http://cancerimmunolres.aacrjournals.org/content/8/12/1470.abstract
AB 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