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Lookup NU author(s): Dr Lei HuangORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2024.Strategies to improve T cell therapy efficacy in solid tumors such as hepatocellular carcinoma (HCC) are urgently needed. The common cytokine receptor γ chain (γc) family cytokines such as IL-2, IL-7, IL-15 and IL-21 play fundamental roles in T cell development, differentiation and effector phases. This study aims to determine the combination effects of IL-21 in T cell therapy against HCC and investigate optimized strategies to utilize the effect of IL-21 signal in T cell therapy. The antitumor function of AFP-specific T cell receptor-engineered T cells (TCR-T) was augmented by exogenous IL-21 in vitro and in vivo. IL-21 enhanced proliferation capacity, promoted memory differentiation, downregulated PD-1 expression and alleviated apoptosis in TCR-T after activation. A novel engineered IL-21 receptor was established, and TCR-T armed with the novel engineered IL-21 receptors (IL-21R-TCR-T) showed upregulated phosphorylated STAT3 expression without exogenous IL-21 ligand. IL-21R-TCR-T showed better proliferation upon activation and superior antitumor function in vitro and in vivo. IL-21R-TCR-T exhibited a less differentiated, exhausted and apoptotic phenotype than conventional TCR-T upon repetitive tumor antigen stimulation. The novel IL-21 receptor in our study programs powerful TCR-T and can avoid side effects induced by IL-21 systemic utilization. The novel IL-21 receptor creates new opportunities for next-generation TCR-T against HCC.
Author(s): Zhu W, Zhang Z, Chen J, Chen X, Huang L, Zhang X, Huang X, Ma N, Xu W, Yi X, Lu X, Fu X, Li S, Mo G, Wang Y, Yuan G, Zang M, Li Q, Jiang X, He Y, Wu S, He Y, Li Y, Hou J
Publication type: Article
Publication status: Published
Journal: Signal Transduction and Targeted Therapy
Year: 2024
Volume: 9
Issue: 1
Online publication date: 20/04/2024
Acceptance date: 07/03/2024
Date deposited: 29/04/2024
ISSN (print): 2095-9907
ISSN (electronic): 2059-3635
Publisher: Springer Nature
URL: https://doi.org/10.1038/s41392-024-01792-6
DOI: 10.1038/s41392-024-01792-6
Data Access Statement: All experimental data generated or analyzed during this study are available from the corresponding authors upon reasonable request. The raw sequence data reported in this paper have been deposited in the Genome Sequence Archive59 in National Genomics Data Center,60 China National Center for Bioinformation / Beijing Institute of Genomics, Chinese Academy of Sciences (GSA-Human: HRA006670 for bulk RNAseq data, HRA006668 for single-cell RNA-seq data) at https://ngdc.cncb.ac.cn/gsahuman
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