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Updated: Jul 29, 2025
An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
Published on: September 12, 2019
TCR T cells overexpressing c-Jun have better functionality with improved tumor infiltration and persistence in
Mohamed S Hussein1, Qi Li1, Rui Mao1
1Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, United States.
Background:
The 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.
Methods:
Recombinant 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.
Results:
We 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.
Conclusion:
c-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.
Insights
Overexpressing c-Jun in T cells enhances their ability to fight hepatocellular carcinoma (HCC). This approach improves T cell expansion, function, and persistence, offering a promising strategy for HCC therapy.
Area of Science:
- Immunology
- Oncology
- Gene Therapy
Background:
- Hepatocellular carcinoma (HCC) has a poor 5-year survival rate (20%), necessitating novel therapeutic strategies.
- T cell receptor (TCR) engineered T cells targeting HLA-A2/alpha fetoprotein (AFP) showed promise against HCC but faced limitations in expansion, function, and persistence.
- c-Jun, a transcription factor crucial for T cell activation, was investigated for its potential to enhance TCR T cell efficacy in HCC models.
Purpose of the Study:
- To investigate if c-Jun overexpression can improve the expansion, function, and persistence of TCR engineered T cells in HCC models.
- To evaluate the impact of c-Jun co-delivery on the antitumor efficacy of AFP-specific TCR T cells.
Main Methods:
- Primary human T cells were transduced using lentiviral vectors to express either an HLA-A2/AFP158-specific TCR or both the TCR and c-Jun (TCR-JUN).
- TCR and TCR-JUN T cells were compared for expansion, effector function, and exhaustion status *in vitro* after HCC tumor stimulation.
- Antitumor effects, persistence, and exhaustion of TCR and TCR-JUN T cells were assessed in HCC xenograft models in NSG mice.
Main Results:
- TCR-JUN T cells demonstrated superior expansion and enhanced functional capacity against HCC tumor cells compared to TCR T cells *in vitro*.
- TCR-JUN T cells exhibited reduced apoptosis and increased resistance to exhaustion following HepG2 tumor stimulation.
- In vivo, c-Jun overexpression boosted TCR T cell expansion, improved infiltration and functionality, reduced exhaustion, and increased overall survival in HCC xenograft models.
Conclusions:
- Overexpression of c-Jun significantly enhances the expansion, function, and persistence of AFP-specific TCR engineered T cells.
- Co-delivery of c-Jun holds potential for improving the antitumor efficacy of TCR T cell therapy in patients with HCC.
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