TCR T cells overexpressing c-Jun have better functionality with improved tumor infiltration and persistence in hepatocellular carcinoma

Frontiers in Immunology

Immunology

Rui Mao¹  Mohamed S. Hussein¹  Yibing Peng¹  Qi Li¹  Yukai He² 

[1] Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, United States;Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, United States;Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, United States;

关键词: TCR T cells;    T cell engineering;    adoptive cell therapy;    hepatocellular carcinoma;    tumor immunotherapy;   

DOI  :  10.3389/fimmu.2023.1114770

 received in 2022-12-02, accepted in 2023-04-21,  发布年份 2023

来源: Frontiers

【 摘 要 】

BackgroundThe overall 5-year survival rate of hepatocellular carcinoma (HCC), a major form of liver cancer, is merely 20%, underscoring the need for more effective therapies. We recently identified T cell receptors (TCR) specific for the HLA-A2/alpha fetoprotein amino acids 158-166 (AFP158) and showed that these TCR engineered T cells could control HCC xenografts in NSG mice. However, their efficacy was limited by poor expansion, loss of function, and short persistence of the TCR T cells. Here, we studied whether overexpression of c-Jun, a transcription factor required for T cell activation, in the TCR T cells could enhance their expansion, function, and persistence in HCC tumor models.MethodsRecombinant lentiviral vectors (lv), expressing either the HLA-A2/AFP158-specific TCR or both the TCR and c-Jun (TCR-JUN), were constructed and used to transduce primary human T cells to generate the TCR or TCR-JUN T cells, respectively. We compared the expansion, effector function, and exhaustion status of the TCR and TCR-JUN T cells in vitro after HCC tumor stimulation. Additionally, we studied the persistence and antitumor effects of the TCR and TCR-JUN T cells using the HCC xenografts in NSG mice.ResultsWe could effectively transduce primary human T cells to express both TCR and c-Jun. Compared to the HLA-A2/AFP158 TCR T cells, the TCR-JUN T cells have better expansion potential in culture, with enhanced functional capacity against HCC tumor cells. In addition, the TCR-JUN T cells were less apoptotic and more resistant to exhaustion after HepG2 tumor stimulation. In the HCC xenograft tumor model, c-Jun overexpression enhanced the TCR T cell expansion and increased the overall survival rate of the treated mice. Importantly, the TCR-JUN T cells were less exhausted in the tumor lesions and demonstrated enhanced tumor infiltration, functionality, and persistence.Conclusionc-Jun overexpression can enhance the expansion, function, and persistence of the A2/AFP158 TCR engineered T cells. The c-Jun gene co-delivery has the potential to enhance the antitumor efficacy of AFP specific TCR T cells when treating patients with HCC.

【 授权许可】

Unknown   
Copyright © 2023 Hussein, Li, Mao, Peng and He