RNA结合蛋白(RBPs)的异常调控在肿瘤发生和发展中起着至关重要的作用。但是它们的功能和机制在很大程度上仍然难以捉摸。以前,我们报道了Pumilio1(PUM1),RBP,能调节糖酵解代谢,促进胃癌的进展。然而,PUM1在肿瘤免疫调节中的作用在很大程度上仍然难以捉摸。在这项研究中,我们报道PUM1通过PD-L1在GC中的转录后调控诱导免疫逃逸。我们使用多重免疫组织化学方法分析了GC中PUM1表达与免疫微环境之间的相关性。在体外和体内检查了PUM1缺乏对T细胞的肿瘤杀伤的影响。通过RNA免疫沉淀评估PUM1的分子机制,染色质免疫沉淀,蛋白质印迹,免疫共沉淀,和RNA稳定性分析。临床上,在GC患者中,PUM1表达升高与PD-L1高表达、CD8+T细胞浸润缺失和预后不良相关.PUM1正调节PD-L1表达,PUM1减少增强肿瘤的T细胞杀伤。机械上,PUM1直接与核磷蛋白/核纤溶酶3(NPM3)mRNA结合并稳定NPM3。NPM3与NPM1相互作用以促进NPM1易位到细胞核中并增加PD-L1的转录。PUM1通过PUM1/NPM3/PD-L1轴抑制T细胞的抗肿瘤活性。总之,这项研究揭示了PUM1在调节PD-L1依赖性GC免疫逃逸中的关键转录后效应,从而为癌症免疫治疗提供了一个新的指标和潜在的治疗靶点.
Abnormal regulation of RNA binding proteins (RBPs) plays an essential role in tumorigenesis and progression, but their functions and mechanisms remain largely elusive. Previously, we reported that Pumilio 1 (
PUM1), a RBP, could regulate glycolysis metabolism and promote the progression of gastric cancer (GC). However, the role of
PUM1 in tumor immune regulation remains largely elusive. In this study, we report that PUM1 induces immune escape through posttranscriptional regulation of PD-L1 in GC. We used multiplexed immunohistochemistry to analyze the correlation between PUM1 expression and immune microenvironment in GC. The effect of
PUM1 deficiency on tumor killing of T cells was examined in vitro and in vivo. The molecular mechanism of PUM1 was evaluated via RNA immunoprecipitation, chromatin immunoprecipitation, Western blot, co-immunoprecipitation, and RNA stability assays. Clinically, elevated PUM1 expression is associated with high-expression of PD-L1, lack of CD8+ T cell infiltration and poor prognosis in GC patients.
PUM1 positively regulates PD-L1 expression and
PUM1 reduction enhances T cell killing of tumors. Mechanistically, PUM1 directly binds to nucleophosmin/nucleoplasmin 3 (NPM3) mRNA and stabilizes NPM3. NPM3 interacts with NPM1 to promote NPM1 translocation into the nucleus and increase the transcription of PD-L1.
PUM1 inhibits the anti-tumor activity of T cells through the
PUM1/NPM3/PD-L1 axis. In summary, this study reveals the critical post-transcriptional effect of PUM1 in the modulation of PD-L1-dependent GC immune escape, thus provides a novel indicator and potential therapeutic target for cancer immunotherapy.