THE ROLE OF c-JUN IN ENHANCING TCR-T FUNCTION IN TREATMENT OF HEPATOCELLULAR CARCINOMA

Abstract

Liver cancer is the sixth most common cancer and the third leading cause of cancer death in the world, indicating the treatment gap and the urgent need for novel effective therapies. The majority (90%) of liver cancers are hepatocellular carcinoma (HCC), with an overall 5-year survival rate of ~20%. The efficacy of adoptive cell therapy (ACT) targeting malignant tumors has been limited due to lack of T cell activation in vivo with poor expansion and short persistence of tumor-infiltrating T cells. We proposed that engineering T cells to overexpress c-Jun, a transcription factor required for T cell development and activation, would activate T cells and enhance their persistence, function, and anti-tumor efficacy. In this study, using T-cell receptor- engineered T-cells (TCR-Ts) against the HCC-associated antigen Alfa-fetoprotein (AFP), we demonstrated that human TCR-Ts engineered to overexpress c-Jun (TCR-JUN) have better expansion potential in culture with enhanced functional capacity against HepG2 tumor cells. Additionally, TCR-JUN cells were less apoptotic and more resistant to exhaustion after HepG2 tumor stimulation. In HCC xenograft tumor model, c-Jun overexpression enhanced TCR+ T cell expansion and extended overall survival of the tumor bearing mice. Importantly, the TCR-JUN T cells were less exhausted and demonstrated enhanced tumor infiltration, persistence, and functionality. We conclude that engineering T cells to overexpress c-Jun could be a potential approach to enhance the antitumor efficacy of TCR-Ts.