Pumilio1 regulates NPM3/NPM1 axis to promote PD-L1-mediated immune escape in gastric cancer
Pumilio1 regulates NPM3/NPM1 axis to promote PD-L1-mediated immune escape in gastric cancer
复制标题
DOI：
10.1016/j.canlet.2023.216498
复制
发表时间：
2023-11-29
期刊：
影响因子：
9.7
通讯作者：
Yin，Songcheng
中科院分区：
文献类型：
--
作者：
Wang，Han;Zhou，Zhijun;Yin，Songcheng
RNA结合蛋白（rbp）的异常调控在肿瘤的发生和发展中起着至关重要的作用，但其功能和机制在很大程度上仍然是未知的。此前，我们报道了RBP Pumilio 1 （PUM1）可以调节糖酵解代谢，促进胃癌（GC）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是未知的。在本研究中，我们报道了PUM1通过对GC中PD-L1的转录后调控诱导免疫逃逸。采用多路免疫组化方法分析胃癌组织中PUM1表达与免疫微环境的相关性。体外和体内研究了PUM1缺乏对肿瘤杀伤T细胞的影响。通过RNA免疫沉淀、染色质免疫沉淀、Western blot、共免疫沉淀和RNA稳定性分析来评估PUM1的分子机制。临床上，胃癌患者PUM1表达升高与PD-L1高表达、缺乏CD8+T细胞浸润及预后不良相关。PUM1正调控PD-L1表达，PUM1的减少增强了T细胞对肿瘤的杀伤作用。在机制上，PUM1直接结合核磷蛋白/核纤溶蛋白3 (NPM3) mRNA并稳定NPM3。NPM3与NPM1相互作用，促进NPM1易位进入细胞核，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。综上所述，本研究揭示了PUM1在调节pd - l1依赖性GC免疫逃逸中的关键转录后作用，从而为癌症免疫治疗提供了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 examinedin vitroandin 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.