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

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.

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。

全世界肺癌的发病率和死亡率均居恶性肿瘤的首位。肺癌微环境NK细胞自身功能紊乱，丢失了抗肿瘤能力，肺癌细胞从而逃避了NK细胞的监视。解析促进NSCLC进程的NK细胞关键调控节点分子对干预肺癌的发生发展至关重要。通过本项目研究，发现免疫调节分子Tim-4在肺癌细胞中异常高表达，且与组织浸润NK细胞活性呈负相关。另发现，肺癌组织中IL-6是影响Tim-4表达的独立预测因子，IL-6可以通过转录因子NF-κB促进Tim-4启动子活性，进而上调肺癌细胞Tim-4的表达。另发现，Tim-4通过整合素分子αvβ6及αvβ8促进肺癌细胞细胞因子TGF-β1的产生，还发现肺癌细胞Tim-4通过TGF-β1抑制NK细胞活性，证实RGD基序是肺癌细胞Tim-4对NK细胞产生影响的关键结构。通过该研究，揭示了肺癌细胞Tim-4通过TGF-β1调节NK细胞促进免疫逃逸的新型生物学功能，初步阐明了其在NSCLC发生中的作用机制，为早期干预NSCLC提供了新靶点，具有重要的理论研究价值及潜在的临床应用前景。通过拓展研究，探索了Tim-4在IL-6促进肺癌细胞转移中的作用，通过该研究不但拓展了免疫分子Tim-4的新的生物学功能，而且对于肺癌的转移机制提供了新的线索。在本项目的实施下，1人晋升正高级职称，部分研究结果发表SCI收录论文2篇，授权实用新型专利1项。