转录因子TOX调控自然杀伤细胞功能耗竭的机制探讨

慢性感染或者肿瘤中存在的耗竭免疫细胞是细胞免疫检查点疗法以及其他免疫疗法的重要靶标。肿瘤浸润的NK细胞也呈现出耗竭的表型，但是NK细胞耗竭的发生机制目前还不清楚。最近研究者证明转录因子TOX是耗竭性T细胞产生的关键调节蛋白。我们前期研究发现TOX在肿瘤浸润NK细胞的表达水平明显升高，而且高表达TOX的NK细胞分泌细胞因子以及表达脱颗粒酶CD107a的能力明显低于低表达TOX的NK细胞，推测TOX可能与肿瘤浸润NK细胞功能耗竭有关。该申请拟在前期研究的基础上利用实验室已有的NK细胞发育末端特异性TOX基因缺失的工具小鼠，结合各种肿瘤模型，探讨转录因子TOX对NK细胞免疫监视功能以及功能耗竭的调控作用，并且通过高通量测序技术阐明其作用机制。该研究有望揭示肿瘤浸润NK细胞发生功能耗竭的关键调控因素，对靶向NK细胞免疫治疗具有重要作用。

Exhausted immune cell in chronic infection or tumor is an important target for cellular immune checkpoint therapy and other immunotherapies. Tumor infiltrated NK cells also show exhausted phenotype. However, the mechanism of the exhausted NK cell formation is still unclear. Recently, researchers have demonstrated that the transcription factor TOX is a key regulatory protein for the maintenance of exhausted T cells. Our previous study found that the expression level of TOX in tumor infiltrated NK cells was significantly increased. The ability of NK cells with high expression of TOX to secrete cytokines and to express degranulation enzyme CD107a was significantly lower than that of NK cells with low expression of TOX, suggesting TOX may be related to the exhausted NK cell formation in tumor. On the basis of previous research, we intend to explore the regulatory effect of TOX on the immune surveillance and functional exhaustion of NK cells by using the mice with specific TOX deletion at the end of developmental stage of NK cells and various tumor models in our laboratory, and clarify its mechanism by high-throughput sequencing technology. This study is expected to reveal the key regulatory factor of tumor infiltrating exhausted NK cells, which has an important role in NK cell immunotherapy.