负向免疫调控分子TREM-2在肺癌发病中的作用及机制研究

Overexpression of negative regulatory molecules contribute to the defective immune responses and the promotion of immune escape in tumor microenvironment. Recent studies indicated that TREM-2 paired with DAP12 had a critical role in negative regulation of DC and Mφ activation upon TLR ligation during inflammation. Dispite of the distinctions in the initiation and sustainment of immune response,there were strong similarities between inflammaiton and tumor in immunoregulation,suggesting that TREM-2 might exert as a inhibitory receptor in tumor immunity.Our previous study showed that TREM-2 expression on monocytes was up-regulated in lung cancer patients compared with that of healthy controls, and TREM-2 levels of macrophages increased in malignance in contrast to benign diseases. Moreover, TREM-2 can be induced through mimicking tumor microevironment. Next,we will investigate the effect of TREM-2 on metastasis,chemotherapy and survival among patients,and explore the further mechanism of TREM-2 mediated immune evasion in vitro and in vivo. This study will provide new mechanism for tumor immune escape and inhibitory checkpoint for immunotherapy.

诱导免疫细胞过度表达负向免疫调控分子进而抑制荷瘤机体的免疫功能是肺癌细胞实现免疫逃逸的重要机制之一。TREM-2能够抑制树突状细胞（DC）和巨噬细胞（Mφ）的吞噬功能以及促炎细胞因子的释放而下调炎症反应。肿瘤与炎症尽管在免疫应答的启动和持续方面有着本质区别，但在免疫调节方面存在着不少相似并可互为借鉴之处，因此，我们推测 TREM-2可能参与了肺癌免疫逃逸的发生。先期研究发现肺癌患者外周血中单核细胞表达TREM-2的比例及丰度均较健康者增高、恶性病变者手术标本切片中Mφ的TREM-2表达高于良性者以及肿瘤微环境可以诱导DC过表达TREM-2。本项目拟进一步分析TREM-2与肺癌转移、化疗疗效以及患者远期生存的关系；通过体内外实验探讨TREM-2介导的肺癌免疫逃逸发生的分子机制以及所需的下游信号通路。该项目的完成有望为肺癌免疫逃逸机制增添新的认识，为筛选肺癌免疫治疗的新靶点提供一定的理论依据。