分泌sPD-1的CAR-T对B-NHL的抗肿瘤作用及机制研究

嵌合抗原受体T细胞（chimeric antigen receptor–T cells，CAR-T）对B细胞非霍奇金淋巴瘤（B-cell non-Hodgkin lymphoma，B-NHL）的疗效仍亟待提高，通过CAR-T改造克服程序性死亡因子（programmed death 1，PD-1）及其配体PD-L1抑制信号的策略极具潜力但仍在不断探索中。本研究首次设计了分泌可溶性PD-1（sPD-1）的CAR-T并通过体内外实验证明其增强对过表达PD-L1的B细胞肿瘤的抗肿瘤活性并改善CAR-T细胞分化、耗竭及代谢表型。本研究提出假设sPD-1具有与mPD-L1结合并促进肿瘤抗凋亡作用并拟在研究中证明，同时进一步研究sPD1-CAR-T对表达内源性PD-L1的B细胞淋巴瘤细胞的抗肿瘤活性及起效机制。

The efficacy of chimeric antigen receptor-T (CAR-T) cell in the treatment of B-cell non-Hodgkin lymphoma (B-NHL) needs to be improved urgently. The strategies of combining CAR-T cell and programmed death 1 (PD-1)/PD-L1 axis blockade are promising but still need further investigation. We firstly designed CAR-T cell secreting soluble PD-1 (sPD-1) and demonstrated its anti-tumor activity against B-cell malignancies over-expressing PD-L1 in vivo and in vitro. Meanwhile, it was proved that sPD-1 is important for improving differentiation, exhausted, and metabolic phenotypes of CAR-T cell. This study proposes the hypothesis that sPD-1 could bind to mPD-L1 and promote anti-apoptosis of tumor, which was planned to be proved in this study. Meanwhile, the anti-tumor activity of sPD1-CAR-T cells on B-cell lymphoma cells expressing endogenous PD-L1 and the mechanism behind will be further investigated.