Suzhou Cancer Center Core Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Baita West Road #16, Suzhou, 215001, China

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Published Online:4 Jan 2023https://doi.org/10.2217/imt-2022-0171

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Abstract

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.

Plain language summary

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.

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Papers of special note have been highlighted as: • of interest; •• of considerable interest

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Vol. 14, No. 18

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History

Received 4 July 2022

Accepted 1 December 2022

Published online 4 January 2023

Published in print December 2022

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Keywords

Author contributions

TP Xu, M Sun and EX Wang designed and supervised the study. TP Xu and XM Chen conducted the in vitro and in vivo experiments. J Bai and C Wang contributed to the acquisition of results and performed the data analysis. EX Wang and M Sun wrote the manuscript. All authors read and approved the final manuscript.

Financial & competing interests disclosure

This work was supported by the National Natural Science Foundation of China (82060559 to EX Wang) and the Natural Science Foundation of Guangxi Province (2019JJA140045). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

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

Abstract

Plain language summary

References