c-Met-targeted chimeric antigen receptor T cells inhibit hepatocellular carcinoma cells in vitro and in vivo
Xiaochen Huang1
Jiaojiao Guo2
Tao Li3
Lizhou Jia2
Xiaojun Tang3
Jin Zhu4
Qi Tang2
Zhenqing Feng5
1.National Health Commission Key Laboratory of Antibody Techniques,Nanjing Medical University,Nanjing,Jiangsu 211166,China;Department of Pathology,Nanjing Medical University,Nanjing,Jiangsu 211166,China;Departments of Pathology,Jiangsu Cancer Hospital Affiliated to Nanjing Medical University,Jiangsu Province Institute of Cancer,Nanjing,Jiangsu 210009,China2.National Health Commission Key Laboratory of Antibody Techniques,Nanjing Medical University,Nanjing,Jiangsu 211166,China;Department of Pathology,Nanjing Medical University,Nanjing,Jiangsu 211166,China3.National Health Commission Key Laboratory of Antibody Techniques,Nanjing Medical University,Nanjing,Jiangsu 211166,China4.Huadong Medical Institute of Biotechniques,Nanjing,Jiangsu 210002,China5.National Health Commission Key Laboratory of Antibody Techniques,Nanjing Medical University,Nanjing,Jiangsu 211166,China;Department of Pathology,Nanjing Medical University,Nanjing,Jiangsu 211166,China;Jiangsu Key Lab of Cancer Biomarkers,Prevention and Treatment,Collaborative Innovation Center for Cancer Personalized Medicine,Nanjing Medical University,Nanjing,Jiangsu 211166,China
摘要：c-Met is a hepatocyte growth factor receptor overexpressed in many tumors such as hepatocellular carcinoma(HCC).Therefore,c-Met may serve as a promising target for HCC immunotherapy.Modifying T cells to express c-Met-specific chimeric antigen receptor(CAR)is an attractive strategy in treating c-Met-positive HCC.This study aimed to systematically evaluate the inhibitory effects of 2nd-and 3rd-generation c-Met CAR-T cells on hepatocellular carcinoma(HCC)cells.Here,2nd-and 3rd-generation c-Met CARs containing an anti-c-Met single-chain variable fragment(scFv)as well as the CD28 signaling domain and CD3ζ(c-Met-28-3ζ),the CD 137 signaling domain and CD3ζ(c-Met-137-3ζ),or the CD28 and CD137 signaling domains and CD3ζ(c-Met-28-137-3ζ)were constructed,and their abilities to target c-Met-positive HCC cells were evaluated in vitro and in vivo.All c-Met CARs were stably expressed on T cell membrane,and c-Met CAR-T cells aggregated around c-Met-positive HCC cells and specifically killed them in vitro.c-Met-28-137-3ζ CAR-T cells secreted more interferon-gamma(IFN-γ)and interleukin 2(IL-2)than c-Met-28-3ζ CAR-T cells and c-Met-137-3ζ CAR-T cells.Compared with c-Met low-expressed cells,c-Met CAR-T cells secreted more cytokines when co-cultured with c-Met high-expressed cells.Moreover,c-Met-28-137-3ζ CAR-T cells eradicated HCC more effectively in xenograft tumor models compared with the control groups.This study suggests that 3rd-generation c-Met CAR-T cells are more effective in inhibiting c-Met-positive HCC cells than 2nd-generation c-Met CAR-T cells,thereby providing a promising therapeutic intervention for c-Met-positive HCC.
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分类号：R730.51(一般性问题)
论文发表日期：2022-01-30
在线出版日期：2025-08-15（本平台首次上网日期，不代表文献的发表时间）
页数：12( 10-21 )
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