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

Autor: Hussein MS; Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, United States., Li Q; Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, United States., Mao R; Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, United States., Peng Y; Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, United States., He Y; 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.
Jazyk: angličtina
Zdroj: Frontiers in immunology [Front Immunol] 2023 May 04; Vol. 14, pp. 1114770. Date of Electronic Publication: 2023 May 04 (Print Publication: 2023).
DOI: 10.3389/fimmu.2023.1114770
Abstrakt: 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 (AFP 158 ) 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/AFP 158 -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/AFP 158 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/AFP 158 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.
Competing Interests: Augusta University patented the AFP-specific TCRs that were licensed by Cellular Biomedicine Group, Inc., which is sponsoring a clinical trial for treating HCC NCT03971747. YH and YP are inventors of the patent. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2023 Hussein, Li, Mao, Peng and He.)
Databáze: MEDLINE
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