EBV募集Treg细胞致鼻咽癌细胞免疫逃逸的分子机制研究

Immune suppression induced by regulatory T (Treg) cells is crucial for immune escape of tumors. Recent evidences have shown that immune escape induced by EBV infection promotes the metastasis of nasopharyngeal carcinoma (NPC), but the molecular mechanisms are unclear. Our previous studies showed that the number of Treg cells was positively correlated with EBNA1 expression in NPC specimens, and EBNA1 overexpression could upregulate TGF-β in NPC cell lines, which suppressed the level of miR-200a. Bioinformatics analysis predicted that CXCL12 might be the target gene of miR-200a. Based on the critical role of CXCL12/CXCR4 axis in Treg recruitment, we speculated that EBV infection might activate TGF-β/miR-200a/CXCL12 signal pathway to recruit Treg in NPC, which induced immune escape. In this project, we will explore the association between Treg and EBV infection with NPC tissue and blood samples. Next, we will prove the TGF-β/miR-200a/CXCL12 signal pathway, by which EBV infection to recruit Treg. Finally, we will analyze the effects of this pathway activation on the functions of Treg cells. We aim to elucidate the molecular mechnisams of NPC immune escape mediated by Treg recruitment induced by EBV infection, which will provide new understandings towards the molecular mechanisms of EBV infection in NPC tumorigenesis and new targets of EBV-targeted immunotherapy in NPC.

Treg介导免疫抑制是肿瘤免疫逃逸的重要机制。研究表明，EBV诱导免疫逃逸促进鼻咽癌转移而预后不良，但机制尚未明了。我们前期发现癌组织EBNA1与Treg呈正比；在癌细胞过表达EBNA1可上调TGF-β和下调miR-200a，CXCL12被预测为miR-200a靶基因。基于CXCL12/CXCR4轴在募集Treg中的重要作用，我们推测EBV可能通过激活TGF-β/miR-200a/CXCL12通路募集Treg致鼻咽癌免疫逃逸。本课题拟通过临床资料证实EBV诱导鼻咽癌免疫逃逸与Treg相关；通过体内外实验证实EBNA1激活TGF-β/miR-200a/CXCL12通路募集Treg；通过细胞共培养探讨EBV感染对Treg免疫抑制功能的影响及信号通路，阐明EBV募集Treg发挥免疫抑制致鼻咽癌免疫逃逸的分子机制。本研究对深入理解EBV参与鼻咽癌发病机制和完善EBV为靶点的免疫治疗具有重要意义。

Treg介导免疫抑制是肿瘤免疫逃逸的重要机制。既往研究表明，EBV诱导免疫逃逸促进鼻咽癌转移而预后不良，但机制尚未明了。本项目旨在阐明EBV募集Treg致鼻咽癌免疫逃逸的分子机制。项目实施过程中对原研究内容进一步拓展，不仅证实EBV通过激活下游TGF-β1/miR-200a/CXCL12通路趋化募集Treg，还进一步表明EBV可通过上调TGF-β1诱导幼稚型T细胞转化为成熟Treg，上述研究结果表明EBV可通过趋化募集和诱导分化双机制作用于Treg从而促进鼻咽癌免疫逃逸。此外，本项目还针对EBV相关鼻咽癌免疫微环境进行深入研究，分析包括Treg、NK细胞等多种免疫细胞在微环境中的分布和密度，阐明其与患者预后的相关性。本研究的顺利完成为深入理解EBV的致癌机制及完善以EBV为靶点的鼻咽癌免疫治疗具有重要意义。