Rationale: Protein arginine methyltransferase 5 (PRMT5) is an oncogene that promotes tumor cell proliferation, invasion and metastasis. However, the underlying mechanisms by which PRMT5 contributes to the progression of cervical cancer and especially the tumor microenvironment remain poorly understood. Methods: PRMT5 expression level was analyzed by Q-PCR, western blot, immunohistochemistry, and TCGA database. The role of PRMT5 in tumor growth was observed by transplanted tumor models, and the function of T cells in tumor microenvironment and in vitro co-culture system was investigated through flow cytometry. The transcriptional regulation of PRMT5 was analyzed using luciferase reporter and chromatin immunoprecipitation (ChIP) assay. The therapeutic effect of PRMT5 inhibitor was evaluated in a cervical cancer cell line transplanted tumor model. Results: We observed that the mRNA and protein expression levels of PRMT5 were increased in cervical cancer tissues, and the high expression of PRMT5 was associated with poor outcomes in cervical cancer patients. The absence of PRMT5 significantly inhibited tumor growth in a cervical cancer transplanted tumor model, and importantly, PRMT5 absence in tumors led to increase the number and enhance the function of tumor infiltrating T cells. Mechanistically, PRMT5 enhanced the transcription of STAT1 through symmetric dimethylation of histone H3R2 and thus promoted PD-L1 expression in cervical cancer cells. Moreover, in an in vitro co-culture system, knockdown of PRMT5 in tumor cells could directly enhance the expression of IFN-γ, TNF-α and granzyme B in T cells. These results suggested that PRMT5 promoted the development of cervical cancer by the crosstalk between tumor cells and T cells. Furthermore, the PRMT5 inhibitor EPZ015666 treatment could suppress tumor growth in a cervical cancer transplanted tumor model. Conclusion: Our results clarify a new mechanism which PRMT5 knockdown in cervical cancer cells drives an antitumor function via reprogramming T cell-mediated response and regulating PD-L1 expression. Thus, our study highlights that PRMT5 may be a potential target for cervical cancer therapy.

中文翻译：

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PRMT5 破坏通过重编程 T 细胞介导的反应和调节 PD-L1 表达来驱动宫颈癌的抗肿瘤免疫。

基本原理：蛋白质精氨酸甲基转移酶 5 (PRMT5) 是一种促进肿瘤细胞增殖、侵袭和转移的癌基因。然而，PRMT5 促进宫颈癌进展，尤其是肿瘤微环境进展的​​潜在机制仍然知之甚少。方法：通过Q-PCR、蛋白质印迹、免疫组化和TCGA数据库分析PRMT5的表达水平。通过移植肿瘤模型观察PRMT5在肿瘤生长中的作用，并通过流式细胞术研究T细胞在肿瘤微环境和体外共培养系统中的功能。使用荧光素酶报告基因和染色质免疫沉淀 (ChIP) 测定分析 PRMT5 的转录调控。在宫颈癌细胞系移植肿瘤模型中评估 PRMT5 抑制剂的治疗效果。结果：我们观察到 PRMT5 的 mRNA 和蛋白表达水平在宫颈癌组织中升高，并且 PRMT5 的高表达与宫颈癌患者的不良预后相关。在宫颈癌移植肿瘤模型中，PRMT5 的缺失显着抑制了肿瘤的生长，重要的是，肿瘤中 PRMT5 的缺失导致肿瘤浸润 T 细胞的数量增加和功能增强。从机制上讲，PRMT5 通过组蛋白 H3R2 的对称二甲基化增强 STAT1 的转录，从而促进宫颈癌细胞中 PD-L1 的表达。此外，在体外共培养系统中，肿瘤细胞中 PRMT5 的敲低可直接增强 T 细胞中 IFN-γ、TNF-α 和颗粒酶 B 的表达。这些结果表明PRMT5通过肿瘤细胞和T细胞之间的串扰促进了宫颈癌的发展。此外，PRMT5 抑制剂 EPZ015666 治疗可以抑制宫颈癌移植肿瘤模型中的肿瘤生长。结论：我们的研究结果阐明了宫颈癌细胞中 PRMT5 敲低通过重编程 T 细胞介导的反应和调节 PD-L1 表达来驱动抗肿瘤功能的新机制。因此，我们的研究强调 PRMT5 可能是宫颈癌治疗的潜在靶点。我们的研究结果阐明了宫颈癌细胞中 PRMT5 敲低通过重编程 T 细胞介导的反应和调节 PD-L1 表达来驱动抗肿瘤功能的新机制。因此，我们的研究强调 PRMT5 可能是宫颈癌治疗的潜在靶点。我们的研究结果阐明了宫颈癌细胞中 PRMT5 敲低通过重编程 T 细胞介导的反应和调节 PD-L1 表达来驱动抗肿瘤功能的新机制。因此，我们的研究强调 PRMT5 可能是宫颈癌治疗的潜在靶点。