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

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

Source：Molecular Therapy-Oncolytics, 2022, 26: 15-26.

DOI：10.1016/j.omto.2022.06.003

• RECEPTOR
• LIGANDS
• COSTIMULATION
• LEUKEMIA
• THERAPY

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-antigentargeting 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 GPC3DAP10-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.

• Institution
  中国科学院; 广州医学院; 南方医科大学; 中国科学院研究生院