CD81对嵌合抗原受体/抗原相互作用力—化耦联特性的调控机制研究

嵌合抗原受体（CAR）T细胞特异性识别B细胞表面的CD19，能有效识别并杀伤急性B细胞淋巴细胞白血病（B-ALL）病人的肿瘤细胞。然而，复发仍是导致CD19-CAR-T治疗失败的主要原因之一。针对CD19阳性复发病人，再次回输CAR-T细胞并不能有效清除其体内的肿瘤细胞。这些CD19阳性肿瘤细胞如何逃逸CD19-CAR-T细胞杀伤并不清楚。目前有研究表明，肿瘤B细胞表面的CD81表达量与正常B细胞相比出现了不同程度的改变，而CD81能通过与细胞膜内的胆固醇互作改变其与CD19的连接，潜在改变CD19的空间取向从而可能影响CAR对CD19的原位识别。此外，CAR/CD19的原位互作还潜在受到多种生物力的调控。因此，本项目拟系统研究CD81对CAR/CD19原位互作力—化耦联特性的调控机制，并研究其对CAR-T细胞杀伤效率的影响，潜在为提升CAR-T细胞治疗长期有效率提供新的优化思路。

Chimeric antigen receptor (CAR) T cells specifically target CD19 on B cells to efficiently recognize and eliminate the tumor cells in patients with B-cell acute lymphoblastic leukemia (B-ALL). However, relapse is still one of the primary reasons leading to the failure of CD19-CAR-T cell therapy. The reinfusion of CAR-T cells into patients with CD19-positive relapse fails to efficiently eliminate their tumor cells. The detailed mechanism underlying this immune escape still remains unclear. It has been reported that the CD81 expression levels on tumor B cells exhibit heterogeneous alterations in comparison to those on normal B cells. Moreover, the CD81/CD19 ligation is modulated by the interaction between CD81 and cholesterol in the cell membrane, which potentially alters the spatial orientation of CD19 and thus regulates CAR/CD19 recognition. Besides, the in-situ CAR/CD19 interactions are potentially regulated by the surrounding biomechanical forces. Therefore, we aim to systematically dissect the regulatory mechanisms of CD81 on the mechanical-chemical coupling of the in-situ CAR/CD19 interaction and their influences on the killing efficacies of CAR-T cells, which would potentially bring new ideas about how to improve the long-term efficacy of CAR-T cell therapy.