State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Institute of Cellular Medicine, Newcastle University Medical School, Newcastle, UK.
Signal Transduct Target Ther. 2024 Apr 20;9(1):101. doi: 10.1038/s41392-024-01792-6.
Strategies to improve T cell therapy efficacy in solid tumors such as hepatocellular carcinoma (HCC) are urgently needed. The common cytokine receptor γ chain (γ) 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.
迫切需要提高 T 细胞疗法在实体瘤（如肝细胞癌[HCC]）中的疗效的策略。常见的白细胞介素 2（IL-2）、IL-7、IL-15 和 IL-21 等共同的细胞因子受体 γ 链（γ）家族细胞因子在 T 细胞的发育、分化和效应阶段发挥着重要作用。本研究旨在确定 IL-21 在针对 HCC 的 T 细胞治疗中的组合作用，并研究优化利用 IL-21 信号在 T 细胞治疗中的作用的策略。在体外和体内，外源性 IL-21 增强了 AFP 特异性 T 细胞受体工程 T 细胞（TCR-T）的抗肿瘤功能。IL-21 增强了 TCR-T 的增殖能力，促进了记忆分化，下调了 TCR-T 激活后的 PD-1 表达并减轻了凋亡。建立了一种新型的工程化 IL-21 受体，携带新型工程化 IL-21 受体（IL-21R-TCR-T）的 TCR-T 在没有外源性 IL-21 配体的情况下表现出上调的磷酸化 STAT3 表达。IL-21R-TCR-T 在激活后表现出更好的增殖能力，并且在体外和体内均具有更好的抗肿瘤功能。与常规 TCR-T 相比，IL-21R-TCR-T 在重复肿瘤抗原刺激下表现出较少分化、衰竭和凋亡表型。我们研究中的新型 IL-21 受体可对 TCR-T 进行编程，并且可以避免 IL-21 全身利用引起的副作用。新型 IL-21 受体为针对 HCC 的下一代 TCR-T 创造了新的机会。
