WTAP Accelerates Exhaustion of CD8+ T Cells and Progression of Hepatocellular Carcinoma by Promoting m6A Modification and Translation of PD1 mRNA.

IF 4.4 3区 医学 Q2 CELL BIOLOGY
Mediators of Inflammation Pub Date : 2025-06-18 eCollection Date: 2025-01-01 DOI:10.1155/mi/6217272
Rong Li, Shunle Li, Hua Li, Bingli Liu, Zimu Wang, Huanqin Lei, Yuting Li, Lijuan Jia, Junhui Li, Hongwei Lu, Meng Xu
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引用次数: 0

Abstract

The N6-methyladenosine (m6A) methylase WTAP has been identified as a proto-oncogene in multiple cancers, including hepatocellular carcinoma (HCC). Interestingly, although WTAP expression does not differ between normal liver and HCC tissues or across different stages of HCC, patients with higher WTAP expression exhibit significantly shorter median survival times (MSTs). Here, we found that WTAP was upregulated in tumor-infiltrating CD8+ T cells, which were more enriched in HCC patients compared to the controls. HCC patients also displayed higher PD1 levels and a greater proportion of exhausted CD8+ T cells (TCF+ PD1+). Moreover, WTAP promoted PD1 expression and suppressed the proliferation and immune activity of CD8+ T cells. In the co-culture system, WTAP-overexpressing CD8+ T cells enhanced the malignancy of HCC cells. Notably, WTAP silencing further augmented the boosting effect of PD1 silencing on CD8+ T cell immune activity and strengthened its inhibitory effect on HCC cell growth. As an m6A "writer", WTAP increased the m6A level of PD1 mRNA, thereby promoting YTHDF1-mediated translation of PD1. Finally, in the HuNSG xenograft tumor model, WTAP knockdown not only alleviated CD8+ T cell exhaustion and inhibited tumor progression but also synergistically enhanced the antitumor efficacy of anti-PD1 therapy. In conclusion, WTAP promoted CD8+ T cell exhaustion and HCC progression by facilitating the m6A modification and translation of PD1 mRNA.

WTAP通过促进m6A修饰和PD1 mRNA的翻译加速CD8+ T细胞的衰竭和肝细胞癌的进展。
n6 -甲基腺苷(m6A)甲基化酶WTAP已被确定为多种癌症的原癌基因,包括肝细胞癌(HCC)。有趣的是,尽管WTAP表达在正常肝脏和HCC组织之间以及HCC的不同阶段没有差异,但WTAP表达较高的患者的中位生存时间(MSTs)明显较短。在这里,我们发现WTAP在肿瘤浸润性CD8+ T细胞中上调,与对照组相比,HCC患者的CD8+ T细胞更丰富。HCC患者也表现出更高的PD1水平和更大比例的耗尽CD8+ T细胞(TCF+ PD1+)。此外,WTAP可促进PD1的表达,抑制CD8+ T细胞的增殖和免疫活性。在共培养系统中,过表达wtap的CD8+ T细胞增强了HCC细胞的恶性性。值得注意的是,WTAP沉默进一步增强了PD1沉默对CD8+ T细胞免疫活性的促进作用,增强了其对HCC细胞生长的抑制作用。WTAP作为m6A的“撰写者”,增加了PD1 mRNA的m6A水平,从而促进ythdf1介导的PD1翻译。最后,在HuNSG异种移植肿瘤模型中,WTAP敲低不仅可以缓解CD8+ T细胞衰竭,抑制肿瘤进展,还可以协同增强抗pd1治疗的抗肿瘤效果。综上所述,WTAP通过促进m6A修饰和pd1mrna的翻译促进CD8+ T细胞衰竭和HCC进展。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Mediators of Inflammation
Mediators of Inflammation 医学-免疫学
CiteScore
8.70
自引率
0.00%
发文量
202
审稿时长
4 months
期刊介绍: Mediators of Inflammation is a peer-reviewed, Open Access journal that publishes original research and review articles on all types of inflammatory mediators, including cytokines, histamine, bradykinin, prostaglandins, leukotrienes, PAF, biological response modifiers and the family of cell adhesion-promoting molecules.
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