GPC3-targeted CAR-T cells expressing GLUT1 or AGK exhibit enhanced antitumor activity against hepatocellular carcinoma  

作　　者：Rui-xin Sun Yi-fan Liu Yan-sha Sun Min Zhou Yi Wang Bi-zhi Shi Hua Jiang Zong-hai Li 

机构地区：[1]State Key Laboratory of Systems Medicine for Cancer,Shanghai Cancer Institute,Renji Hospital,Shanghai Jiaotong University School of Medicine,Shanghai,200032,China [2]Department of Laboratory Medicine,Shanghai Tongji Hospital,School of Medicine,Tongji University,Shanghai,200065,China [3]CARsgen Therapeutics,Shanghai,200032,China

出　　处：《Acta Pharmacologica Sinica》2024年第9期1937-1950,共14页中国药理学报（英文版）

基　　金：National Natural Science Foundation of China(ID 82073358 to Hua Jiang,ID 82073359 to Zonghai Li,82272920 to Min Zhou);Shanghai Municipal Health and Health Commission(ID 20234Y0193 to Sun Ruixin);Shanghai Oriental Talent Youth Project(to Sun Ruixin);Shanghai“Rising Stars of Medical Talents”Youth Development Program-Clinical Laboratory Practitioner Program(ID 2023-JY to Sun Ruixin);“Gan Quan Xin Xing”talent training program of Shanghai Tongji Hospital(HRBC 2307).

摘　　要：Chimeric antigen receptor-expressing T(CAR-T)cells induce robust antitumor responses in patients with hematologic malignancies.However,CAR-T cells exhibit only limited efficacy against solid tumors such as hepatocellular carcinoma(HCC),partially due to their limited expansion and persistence.CD8^(+)T cells,as key components of the adaptive immune response,play a central role in antitumor immunity.Aerobic glycolysis is the main metabolic feature of activated CD8^(+)T cells.In the tumor microenvironment,however,the uptake of large amounts of glucose by tumor cells and other immunosuppressive cells can impair the activation of T cells.Only when tumor-infiltrating lymphocytes(TILs)in the tumor microenvironment have a glycolytic advantage might the effector function of T cells be activated.Glucose transporter type 1(GLUT1)and acylglycerol kinase(AGK)can boost glycolytic metabolism and activate the effector function of CD8^(+)T cells,respectively.In this study,we generated GPC3-targeted CAR-T cells overexpressing GLUT1 or AGK for the treatment of HCC.GPC3-targeted CAR-T cells overexpressing GLUT1 or AGK specifically and effectively lysed GPC3-positive tumor cells in vitro in an antigen-dependent manner.Furthermore,GLUT1 or AGK overexpression protected CAR-T cells from apoptosis during repeated exposures to tumor cells.Compared with second-generation CAR-T cells,GPC3-targeted CAR-T cells overexpressing GLUT1 or AGK exhibited greater CD8^(+)T-cell persistence in vivo and better antitumor effects in HCC allograft mouse models.Finally,we revealed that GLUT1 or AGK maintained anti-apoptosis ability in CD8^(+)T cells via activation of the PI3K/Akt pathway.This finding might identify a therapeutic strategy for advanced HCC.

关 键 词：hepatocellular carcinoma GPC3-targeted CAR-T cells glucose transporter type 1 acylglycerol kinase PI3K/Akt pathway 

分 类 号：R735.7[医药卫生—肿瘤]