肺癌细胞Tim-4通过TGF-β1调节NK细胞促进肿瘤免疫逃逸的作用研究

免疫逃逸是肺癌发生发展重要原因，NK细胞是免疫监视主要效应细胞，TGF-β1是其强抑制剂。免疫调节分子Tim-4高表达于NSCLC，促肺癌生长，但对NK细胞免疫应答的影响和机制尚不清楚。前期发现，炎症因子可诱导肺癌细胞表达Tim-4，肺癌组织Tim-4高表达伴浸润NK细胞数目降低，肺癌细胞Tim-4过表达促TGF-β1产生且抑制NK细胞杀伤活性，Tim-4可与整合素分子结合。据此提出假说：肺癌微环境诱导肺癌细胞表达Tim-4，Tim-4通过增强肺癌细胞TGF-β1，抑制NK细胞免疫应答，促进免疫逃逸，加剧肺癌进程。本课题拟从临床标本、多个细胞及肺癌动物模型，研究①肺癌微环境诱导肺癌细胞Tim-4表达机制；②RGD基序在Tim-4促TGF-β1产生中的作用及结合的关键整合素分子；③TGF-β1在Tim-4调控NK细胞中的作用。本研究将为解决肺癌免疫逃逸开阔新思路。

Immune escape is a major cause of lung cancer development. NK cells are the main effector cells executing immune surveillance. TGF-beta 1 is a potent inhibitor of NK cells. Tim-4, an immunoregulatory molecule, was highly expressed in NSCLC, and plays a role in promoting the growth of lung cancer cells. However, the role and mechanism of Tim-4 on NK cell immune response remain unclear. We found that inflammatory factors can induce Tim-4 expressions in lung cancer cells. Moreover, Tim-4 was highly expressed in lung cancer tissues, which the number of infiltrating NK cells was decreased. In addition, Tim-4 overexpression promoted the production of TGF-beta 1 in lung cancer cells, and inhibited killing activity of NK cells. Tim-4 can bind to integrin molecules. Based on these preliminary, we put forward a hypothesis: lung cancer microenvironments induce Tim-4 overexpression in NSCLC, and Tim-4 inhibits NK cell mediated immune response by enhancing TGF-beta 1 production of lung cancer cells, which aggravates the process of lung cancer. In this study, clinical samples, multiple cell and animal models will be used to exploreⅠ) the regulation of tumor microenvironment inducing Tim-4 expression in lung cancer cells, Ⅱ) the effects of RGD motif on Tim-4 promoting TGF-beta 1 production and the key integrin molecules that bind to it, Ⅲ) the role of TGF-beta 1 in the regulation of NK cells by Tim-4 expressed in lung cancer cells. This will open up new ideas for solving immune escape of lung cancer.