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

被引：13

作者：

Li, Shanglin ^{[1
,2
]}

Zhao, Ruocong ^{[3
,12
]}

Zheng, Diwei ^{[1
,2
]}

Qin, Le ^{[1
]}

Cui, Yuanbin ^{[1
,2
]}

Li, Yao ^{[1
,2
]}

Jiang, Zhiwu ^{[1
]}

Zhong, Mengjun ^{[3
]}

Shi, Jingxuan ^{[1
]}

Li, Ming ^{[4
]}

Wang, Xindong ^{[5
]}

Tang, Zhaoyang ^{[6
,7
]}

Wu, Qiting ^{[1
]}

Long, Youguo ^{[1
]}

Hu, Duo ^{[5
]}

Wang, Suna ^{[1
]}

Yao, Yao ^{[1
]}

Liu, Shuang ^{[8
]}

Yang, Li-Hua ^{[9
]}

Zhang, Zhenfeng ^{[10
]}

Tang, Qiannan ^{[11
]}

Liu, Pentao ^{[11
]}

Li, Yangqiu ^{[3
]}

Li, Peng ^{[1
,5
]}

机构：

[1] Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, Key Lab Stem Cell & Regenerat Med,China New Zeala, State Key Lab Resp Dis,Guangdong Prov Key Lab Ste, Guangzhou, Peoples R China

[2] Univ Chinese Acad Sci, Beijing, Peoples R China

[3] Jinan Univ, Inst Hematol, Coll Med, Guangzhou, Peoples R China

[4] Anhui Univ, Hefei, Peoples R China

[5] Guangzhou Regenerat Med & Hlth Guangdong Lab, Bioland Lab, Guangzhou, Peoples R China

[6] Guangdong Zhaotai InVivo Biomed Co Ltd, Guangzhou, Peoples R China

[7] Guangdong Zhaotai Cell Biol Technol Ltd, Foshan, Peoples R China

[8] Guangdong Second Prov Gen Hosp, Dept Hematol, Guangzhou, Peoples R China

[9] Southern Med Univ, Zhujiang Hosp, Dept Pediat Hematol, Guangzhou, Guangdong, Peoples R China

[10] Guangzhou Med Univ, Affiliated Hosp 2, Dept Radiol, Translat Prov Educ Dept,Key Lab Nanoimmmunoregula, Guangzhou, Peoples R China

[11] Univ Hong Kong, Li Ka Shing Fac Med, Sch Biomed Sci Stem Cell & Regenerat Med Consorti, Hong Kong, Peoples R China

[12] Chinese Acad Sci, Hong Kong Inst Sci & Innovat, Ctr Regenerat Med & Hlth, Hong Kong, Peoples R China

来源：

MOLECULAR THERAPY ONCOLYTICS | 2022年 / 26卷

基金：

中国国家自然科学基金;

关键词：

RECEPTOR; LIGANDS; COSTIMULATION; LEUKEMIA; THERAPY;

D O I：

10.1016/j.omto.2022.06.003

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：15 / 26

页数：12

共 33 条

[21] Absence of NKG2D ligands defines leukaemia stem cells and mediates their immune evasion [J].