1区 · 医学
Article
作者: Yu, Mingyan ; Peng, Xueqi ; Zhan, Peng ; Zhao, Fabao ; Li, Mengzhen ; Zong, Runzhe ; Liu, Huiqing ; Liu, Xinyong ; Tian, Xiaoyu ; Li, Zhenyu ; Chen, Chaojia ; Peng, Jiali ; Zhu, Qingfen ; Yue, Xuetian ; Wu, Zhuanchang ; Neckenig, Markus R ; Zhang, Jiwei ; Li, Chunyang ; Tian, Ye ; Ma, Chunhong ; Ma, Shuaiya ; Sheng, Xue ; Li, Yuyang ; Zhao, Fangcheng ; Gao, Lifen ; Liang, Xiaohong ; Li, Yiquan
T cell immunoglobulin and mucin-containing molecule 3 (Tim-3), expressed in dysfunctional and exhausted T cells, has been widely acknowledged as a promising immune checkpoint target for tumor immunotherapy. Here, using a strategy combining virtual and functional screening, we identified a compound named ML-T7 that targets the FG-CC′ cleft of Tim-3, a highly conserved binding site of phosphatidylserine (PtdSer) and carcinoembryonic antigen–related cell adhesion molecule 1 (CEACAM1). ML-T7 enhanced the survival and antitumor activity of primary CD8
+
cytotoxic T lymphocytes (CTLs) and human chimeric antigen receptor (CAR) T cells and reduced their exhaustion in vitro and in vivo. In addition, ML-T7 promoted NK cells’ killing activity and DC antigen-presenting capacity, consistent with the reported activity of Tim-3. ML-T7 strengthened DCs’ functions through both Tim-3 and Tim-4, which is consistent with the fact that Tim-4 contains a similar FG-CC′ loop. Intraperitoneal dosing of ML-T7 showed comparable tumor inhibitory effects to the Tim-3 blocking antibody. ML-T7 reduced syngeneic tumor progression in both wild-type and Tim-3 humanized mice and alleviated the immunosuppressive microenvironment. Furthermore, combined ML-T7 and anti–PD-1 therapy had greater therapeutic efficacy than monotherapy in mice, supporting further development of ML-T7 for tumor immunotherapy. Our study demonstrates a potential small molecule for selectively blocking Tim-3 and warrants further study.