Coexpression of c-Jun in multiple-chain DAP-CAR-engineered T-cells for solid tumor therapy

Aim: This work was designed to explore whether c-Jun overexpression could improve the persistence and antitumor efficacy of DAP chimeric antigen receptor T-cell (CAR-T) cells. Methods: The in vitro and in vivo antitumor effects of mesothelin (MSLN) targeting DAP-CAR-T cells were verified by ELISA, real-time cell analysis and in a xenograft model. Results:c-Jun overexpression did not affect DAP-CAR-T cell expansion while slightly increasing IL-2 secretion. Moreover, c-Jun did not improve the antitumor efficacy of DAP-CAR-T cells in vitro or in vivo, but reduced LAG3 expression and increased the ratio of Tcm and Tn/Tscm cells in vivo. Conclusion: The findings indicate that coexpression with c-Jun in DAP-CAR-T cells slightly improves T-cell exhaustion and central memory phenotype maintenance, which may be useful for DAP-CAR-T cell therapy in solid tumors.Chimeric antigen receptor (CAR) T-cell therapy has achieved great success in treating patients with hematological tumors such as b-acute lymphoblastic leukemia and lymphoma. However, a growing number of clinical trials show that most of the second-generation CAR-T cells with different targeting single-chain fragment variables (scFv) did not exhibit comparable therapeutic effects with CD19-targeting CAR-T cells in solid tumors. To overcome this challenge, scientists have developed several methods to optimize the structure of CARs, including coexpression of a transcription factor called c-Jun in CAR-T cells. The authors previously developed a novel multiple-chain DAP-CAR that shows promising solid tumor eradication capacity. In this study, overexpression of c-Jun only slightly improved the antitumor activity of DAP-CAR-T cells, suggesting other optimization methods are needed.