新型共刺激分子JAML促进CD8+TRMs活化抑制肺癌的机制研究

组织特异性记忆CD8+T细胞(Tissue resident memory CD8+T cells, CD8+TRMs)与肺癌预后正相关，提示CD8+TRMs能够抑制肺癌进展。然而，CD8+TRMs在肺癌微环境内活化的机制尚不清楚。本项目预实验发现：CD8+TRMs特异性表达新型共刺激分子JAML，并在肺癌微环境内显著活化、富集。据此我们假设，JAML选择性促进CD8+TRMs在肺癌微环境内的激活、增殖及生存，活化的CD8+TRMs杀伤肿瘤细胞并启动下游多重免疫应答，最终抑制肺癌进展。本课题拟利用人肺癌生物样本结合基因敲除小鼠肺癌模型，通过体内外实验阐明JAML选择性促进肺癌浸润CD8+TRMs激活的关键机制，探索靶向JAML促进CD8+TRMs活化的潜在干预价值，分析JAML通路关键（细胞）分子与患者临床病理特征及预后的关系，为靶向JAML激活CD8+TRMs的肿瘤防治策略提供新的思路。

Tissue resident memory CD8+T cells (CD8+TRMs) positively correlate with outcomes of multiple human cancers and suggesting they play an anti-tumor role in lung cancer. However, the underling mechanisms of CD8+TRMs activation in lung cancer are still lack. Our previous study found that CD8+TRMs were significantly increased in human lung cancer tissue. Moreover, we found that CD8+TRMs show a pre-activated phenotype. Further study demonstrated that human lung cancer-infiltrating CD8+TRMs expressed high level of JAML, a costimulatory molecule of intraepithelial lymphocytes. Therefore, we hypothesize that the CXADR-JAML signal pathway is selectively activated in cancer-infiltrating CD8+TRMs, and consequently promote the activation and ant-tumor role of cancer-infiltrating CD8+TRMs. Based on our previous study and clinical immune research platform, this project is proposed to uncover the underling mechanism of CXADR-JAML signal pathway in cancer-infiltrating CD8+TRMs activation and their relationship with clinicopathological feature and prognosis of patient. This study will sheds light on the role and critical regulatory mechanism of human CD8+TRMs in lung cancer associated inflammation and tumor progression and also provides novel ideas for clinical targeted intervention to CD8+TRMs or CD8+TRMs associated molecules.