Moderate expression of CD39 in GPC3-CAR-T cells shows high efficacy against hepatocellular carcinoma  

作　　者：Fan Zou Jialiang Wei Jialang Zhuang Yafang Liu Jizhou Tan Xianzhang Huang Ting Liu 

机构地区：[1]Guangdong Cardiovsacular Institute,Guangdong Provincial People’s Hospital,Guangdong Academy of Medical Science,Guangzhou,510080,China [2]The Second Clinical Medical College,Guangzhou University of Chinese Medicine,Department of Laboratory Medicine/State Key Laboratory of Traditional Chinese Medicine Syndrome,Guangdong Provincial Hospital of Chinese Medicine,Guangzhou,510120,China [3]Department of Medical Oncology,The First Affiliated Hospital of Guangxi Medical University,Nanning,530021,China [4]Department of Stomatology,the First Affiliated Hospital,Sun Yat-sen University,Guangzhou,510080,China [5]Medical Research Institute,Guangdong Provincial People’s Hospital(Guangdong Academy of Medical Science),Southern Medical University,Guangzhou,510080,China [6]School of Food and Drug,Shenzhen Polytechnic University,Shenzhen,518055,China [7]Shenzhen Second People’s Hospital,First Affiliated Hospital of Shenzhen University,Shenzhen,518055,China

出　　处：《Frontiers of Medicine》2024年第4期708-720,共13页医学前沿（英文版）

基　　金：supported by grants from the National Natural Science Foundation of China(Nos.82102169,82003252,82202986,82301960);Outstanding Young Talents Seedling Program of Guangdong Hospital of Traditional Chinese Medicine(No.SZ2023QN03);Young Doctor“Sailing”Project of Science and Technology Department of Guangzhou(No.2024A04J3291);Shenzhen Municipal Government of China(No.JCYJ20210324102807019).

摘　　要：CD39 serves as a crucial biomarker for neoantigen-specific CD8^(+)T cells and is associated with antitumor activity and exhaustion.However,the relationship between CD39 expression levels and the function of chimeric antigen receptor T(CAR-T)cells remains controversial.This study aimed to investigate the role of CD39 in the functional performance of CAR-T cells against hepatocellular carcinoma(HCC)and explore the therapeutic potential of CD39 modulators,such as mitochondrial division inhibitor-1(mdivi-1),or knockdown CD39 through short hairpin RNA.Our findings demonstrated that glypican-3-CAR-T cells with moderate CD39 expression exhibited a strong antitumor activity,while high and low levels of CD39 led to an impaired cellular function.Methods modulating the proportion of CD39 intermediate(CD39^(int))-phenotype CAR-T cells such as mdivi-1 and CD39 knockdown enhanced and impaired T cell function,respectively.The combination of mdivi-1 and CD39 knockdown in CAR-T cells yielded the highest proportion of infiltrated CD39^(int)CAR-T cells and demonstrated a robust antitumor activity in vivo.In conclusion,this study revealed the crucial role of CD39 in CAR-T cell function,demonstrated the potential therapeutic efficacy of combining mdivi-1 with CD39 knockdown in HCC,and provided a novel treatment strategy for HCC patients in the field of cellular immunotherapy.

关 键 词：CD39 CAR-T cells mdivi-1 hepatocellular carcinoma antitumor activity 

分 类 号：R735.7[医药卫生—肿瘤]