Tumor Cell–Derived TGFβ1 Attenuates Antitumor Immune Activity of T Cells via Regulation of PD-1 mRNA
Tumor Cell–Derived TGFβ1 Attenuates Antitumor Immune Activity of T Cells via Regulation of PD-1 mRNA
复制标题
肿瘤细胞衍生的 TGFβ1 通过调节 PD-1 mRNA 减弱 T 细胞的抗肿瘤免疫活性
DOI：
10.1158/2326-6066.cir-20-0113
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发表时间：
2020
影响因子：
10.1
通讯作者：
Xuedong Li
中科院分区：
文献类型：
--
作者：
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
T细胞抗肿瘤活性的功能障碍有助于透明细胞肾细胞癌（ccRCC）的肿瘤发生、进展和不良结局，这种功能障碍是由T细胞中程序性细胞死亡-1（PD-1）的高表达引起的。然而，在ccRCC中维持T细胞中高PD-1表达的分子机制尚未得到充分研究。在这里，我们描述了在mRNA水平上调节PD-1的机制，并证明了其对T细胞功能障碍的影响。转录组学分析确定了ccRCC样本中TGFβ1和PD-1 mRNA水平之间的相关性。然后在体外和存活的同基因肿瘤模型中研究PD-1 mRNA调节的潜在机制。我们还观察到TGFβ1在ccRCC患者中具有预后意义，并且其表达与PD-1 mRNA表达相关。CcRCC来源的TGFβ1激活P38并诱导H3上Ser 10的磷酸化，其募集p65以增加T细胞中SRSF 3和SRSF 5的表达。结果，PD-1 mRNA在T细胞中的半衰期延长。SRSF 3与NXF 1协同诱导PD-1 mRNA向T细胞核内转运。然后，我们证明了TGFβ1可以诱导SRSF 3表达以限制T细胞的抗肿瘤活性，这影响了ccRCC小鼠模型中的免疫治疗结果。我们的发现强调了肿瘤来源的TGFβ1介导免疫逃避，并有可能作为ccRCC的预后生物标志物和治疗靶点。
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 investigatedin vitroandin vivousing 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 Ser10on 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