A novel engineered IL-21 receptor arms T-cell receptor-engineered T cells(TCR-T cells)against hepatocellular carcinoma  

作　　者：Wei Zhu Zhiming Zhang Jinzhang Chen Xiaolan Chen Lei Huang Xiaoyong Zhang Xuan Huang Na Ma Weikang Xu Xuan Yi Xinyu Lu Xin Fu Siwei Li Guoheng Mo Yiyue Wang Guosheng Yuan Mengya Zang Qi Li Xiaotao Jiang Yajing He Sha Wu Yukai He Yongyin Li Jinlin Hou 

机构地区：[1]State Key Laboratory of Organ Failure Research,Guangdong Provincial Key Laboratory of Viral Hepatitis Research,Department of Infectious Diseases,Nanfang Hospital,Southern Medical University,Guangzhou,China [2]Institute of Cellular Medicine,Newcastle University Medical School,Newcastle,UK [3]Department of Pathology,The First People’s Hospital of Foshan,Foshan,China [4]Dermatology Hospital,Southern Medical University,Guangzhou,China [5]Department of Immunology,School of Basic Medical Sciences,Southern Medical University,Guangzhou,China [6]Microbiome Medicine Center,Department of Laboratory Medicine,Zhujiang Hospital,Southern Medical University,Guangzhou,China [7]Key Laboratory of Proteomics of Guangdong Province,Demonstration Center for Experimental Education of Basic Medical Sciences of China,Guangzhou,China [8]Medical College of Georgia,Augusta University,112015th Street,Augusta,GA,USA

出　　处：《Signal Transduction and Targeted Therapy》2024年第5期2215-2230,共16页信号转导与靶向治疗（英文）

基　　金：The study was sponsored by the National Key Research and Development Program of China(No.2022YFC2303600);the National Natural Science Foundation of China(82073360 and 81802449);the Guangdong Basic and Applied Basic Research Foundation(2023A1515012169,2021A1515220100,2020A1515011313);the Outstanding Youth Development Scheme of Nanfang Hospital,Southern Medical University(2020J004).

摘　　要：Strategies to improve T cell therapy efficacy in solid tumors such as hepatocellular carcinoma(HCC)are urgently needed.The common cytokine receptorγchain(γc)family cytokines such as IL-2,IL-7,IL-15 and IL-21 play fundamental roles in T cell development,differentiation and effector phases.This study aims to determine the combination effects of IL-21 in T cell therapy against HCC and investigate optimized strategies to utilize the effect of IL-21 signal in T cell therapy.The antitumor function of AFP-specific T cell receptor-engineered T cells(TCR-T)was augmented by exogenous IL-21 in vitro and in vivo.IL-21 enhanced proliferation capacity,promoted memory differentiation,downregulated PD-1 expression and alleviated apoptosis in TCR-T after activation.A novel engineered IL-21 receptor was established,and TCR-T armed with the novel engineered IL-21 receptors(IL-21R-TCR-T)showed upregulated phosphorylated STAT3 expression without exogenous IL-21 ligand.IL-21R-TCR-T showed better proliferation upon activation and superior antitumor function in vitro and in vivo.IL-21R-TCR-T exhibited a less differentiated,exhausted and apoptotic phenotype than conventional TCR-T upon repetitive tumor antigen stimulation.The novel IL-21 receptor in our study programs powerful TCR-T and can avoid side effects induced by IL-21 systemic utilization.The novel IL-21 receptor creates new opportunities for next-generation TCR-T against HCC.

关 键 词：HEPATOCELLULAR TCR utilize 

分 类 号：R735.7[医药卫生—肿瘤]