期刊
PROTEIN & CELL
卷 9, 期 10, 页码 867-878出版社
SPRINGEROPEN
DOI: 10.1007/s13238-017-0384-8
关键词
chimeric antigen receptor; HER2; gastric cancer; cancer stem cell; CD137; immunotherapy
类别
资金
- National Natural Science Foundation of China [81230061, 81402566, 81672319, 81602507, 81602711]
- Science and Technology Planning Project of Beijing City [Z151100003915076]
- key Nursery Project of Chinese PLA General Hospital [16KMZ05]
- National Basic Science and Development Programme of China [2013BAI01B04]
Human epidermal growth factor receptor 2 (HER2) proteins are overexpressed in a high proportion of gastric cancer (GC) cases and affect the maintenance of cancer stem cell (CSC) subpopulations, which are used as targets for the clinical treatment of patients with HER2-positive GC. Despite improvements in survival, numerous HER2-positive patients fail treatment with trastuzumab, highlighting the need for more effective therapies. In this study, we generated a novel type of genetically modified human T cells, expressing a chimeric antigen receptor (CAR), and targeting the GC cell antigen HER2, which harbors the CD137 and CD3 moieties. Our findings show that the expanded CAR-T cells, expressing an increased central memory phenotype, were activated by the specific recognition of HER2 antigens in an MHC-independent manner, and effectively killed patient-derived HER2-positive GC cells. In HER2-positive xenograft tumors, CAR-T cells exhibited considerably enhanced tumor inhibition ability, long-term survival, and homing to targets, compared with those of non-transduced T cells. The sphere-forming ability and in vivo tumorigenicity of patient-derived gastric cancer stem-like cells, expressing HER2 and the CD44 protein, were also inhibited. Our results support the future development and clinical application of this adoptive immunotherapy in patients with HER2-positive advanced GC.
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