DAP10 integration in CAR-T cells enhances the killing of heterogeneous tumors by harnessing endogenous NKG2D

Shanglin Li, Ruocong Zhao, Diwei Zheng, Le Qin, Yuanbin Cui, Yao Li, Zhiwu Jiang, Mengjun Zhong, Jingxuan Shi, Ming Li, Xindong Wang, Zhaoyang Tang, Qiting Wu, Youguo Long, Duo Hu, Suna Wang, Yao Yao, Shuang Liu, Li-Hua Yang, Zhenfeng Zhang, Qiannan Tang, Pentao Liu, Yangqiu Li, Peng Li

Molecular Therapy-Oncolytics

2022, 26, , 15-26

Peng Li

6.311

 Although chimeric antigen receptor T (CAR-T) cells have achieved remarkable successes in hematological malignancies, the efficacies of CAR-T cells against solid tumors remains unsatisfactory. Heterogeneous antigen expression is one of the obstacles on its effective elimination of solid cancer cells. DNAX-activating protein 10 (DAP10) interacts with natural killer group 2D (NKG2D), acting as an adaptor that targets various malignant cells for surveillance. Here, we designed a DAP10 chimeric receptor that utilized native NKG2D on T cells to target NKG2D ligand-expressing cancer cells. We then tandemly incorporated it with anti-glypican 3 (GPC3) single-chain variable fragment (scFv) to construct a dual-antigen-targeting system. T cells expressing DAP10 chimeric receptor (DAP10-T cells) displayed with an enhancement on both cytotoxicity and cytokine secretion against solid cancer cell lines, and its tandem connection with anti-GPC3 scFv (CAR GPC3-DAP10-T cells) exhibited a dual-antigen-targeting capacity on eliminating heterogeneous cancer cells in vitro and suppressing the growth of heterogeneous cancer in vivo. Thus, this novel dual-targeting system enabled a high efficacy on killing cancer cells and extended the recognition profile of CAR-T cells toward tumors, which providing a potential strategy on treatment of solid cancer clinically.