Herpes Virus Entry Mediator Costimulation Signaling Enhances CAR T-cell Efficacy Against Solid Tumors Through Metabolic Reprogramming
Shishuo Sun, Chao Huang, Mengmeng Lü, Heng Xu, Yifan Yuan, Wanxin Zhao, Xiaolei Hu, Bixi Wang, Wei Zhang, Xiaoge Gao, Junnian Zheng, Lishan Su, Qing Zhang
Abstract
Costimulatory domains (CSD) of 4-1BB and CD28 are most widely used in chimeric antigen receptor (CAR)-engineered T cells. These CAR T cells have shown encouraging efficacy in the treatment of hematologic malignancies but have limited efficacy in solid tumors. The herpes virus entry mediator (HVEM) is a costimulatory molecule with a novel downstream signaling pathway. In response to target cells, CAR T cells with a HVEM CSD (HVEM-CAR T) displayed more robust cytokine release and cytotoxicity than 4-1BB-CAR T or CD28-CAR T in vitro. Furthermore, HVEM-CAR T showed superior therapeutic efficacy in several mouse tumor models. Mechanistically, the HVEM CSD endowed CAR T cells with attenuated exhaustion, improved function and persistence, and enhanced metabolic activities in tumor tissue compared with 4-1BB-based or CD28-based CAR T cells. These studies establish that the HVEM CSD has the potential to improve the therapeutic efficacy of CAR T cells against solid tumors.