环状RNAcircEIF3B作为转录促进子调节HIF-1α介导Gal-9转录诱导非小细胞肺癌免疫逃逸的机制研究

免疫逃逸是肿瘤发生、发展的关键因素，机制复杂。研究显示，环状RNA异常是肿瘤免疫逃逸的重要原因之一，然而其作为转录促进子发挥作用的机理尚不明确。我们预实验发现环状EIF3B主要定位于细胞核，在PD1抗体耐药的非小细胞肺癌组织中高表达，且与肿瘤组织CD8+T和NK细胞浸润负相关。体外实验进一步提示环状EIF3B与HIF-1α间有相互作用，并可以上调Gal-9表达。近来文献证实Gal-9作为肿瘤微环境中重要的免疫抑制因子，参与PD1抗体治疗耐药。据此推测环状EIF3B通过促进HIF-1α对Gal-9转录诱导CD8+T和NK细胞功能耗竭。本课题拟通过临床组织样本揭示环状EIF3B和Gal-9表达、CD8+T和NK细胞浸润以及患者预后的关系；细胞与动物水平阐明环状EIF3B通过HIF-1α调控Gal-9转录的机制；初步揭示NSCLC免疫逃逸新机制及潜在治疗新靶点。

Immune evasion plays a critical role in tumorigenesis and progression. Studies have shown that dysregulation of circular RNA (circRNA) is one of the vital reasons for cancer immune evasion. However, the mechanism of circRNA as a transcriptional promoter is still unclear. Our preliminary experiments found that circular EIF3B (circEIF3B) is mainly localized in the nucleus. The higher circEIF3B levels in non-small cell lung cancer (NSCLC) patient tissues were correlated with resistance to PD1 antibody therapy and reduced CD8+T and NK cell infiltration. Furthermore, in vitro experiments suggest that circular EIF3B interacted with HIF-1α, and then up-regulated the Gal-9 expression in NSCLC cells. Recent studies have reported that Gal-9 is an important immunosuppressive factor in the tumor microenvironment and is involved in the process of inducing resistance to PD1 antibody therapy. Therefore, we speculated that circEIF3B induced CD8+T and NK cell exhaustion by promoting HIF-1α-mediated Gal-9 transcription. This study intends to reveal the relationship among circEIF3B and Gal-9 expression, CD8+T and NK cell infiltration, and patient prognosis in clinical tissue samples. In addition, the study aims to elucidate the mechanism of circEIF3B in regulating HIF-1α-mediated Gal-9 transcription in NSCLC cells and animals. Our project will provide novel insights into the mechanisms of immune evasion and potential therapy targets for the treatment of NSCLC.