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_c) 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 细胞治疗肝细胞癌 (HCC) 等实体瘤疗效的策略。常见细胞因子受体 γ 链 (γ _c ) 家族细胞因子，如 IL-2、IL-7、IL-15 和 IL-21 在 T 细胞发育、分化和效应阶段发挥重要作用。本研究旨在确定 IL-21 在 T 细胞治疗中对 HCC 的联合作用，并研究利用 IL-21 信号在 T 细胞治疗中的作用的优化策略。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激活后可增强TCR-T的增殖能力，促进记忆分化，下调PD-1表达并减轻细胞凋亡。建立了一种新型工程化 IL-21 受体，并且配备新型工程化 IL-21 受体 (IL-21R-TCR-T) 的 TCR-T 在没有外源性 IL-21 配体的情况下显示出上调的磷酸化 STAT3 表达。 IL-21R-TCR-T 在激活后表现出更好的增殖能力，并且在体外和体内表现出优异的抗肿瘤功能。 IL-21R-TCR-T 在重复肿瘤抗原刺激后表现出比传统 TCR-T 更低的分化、耗尽和凋亡表型。我们研究中的新型IL-21受体可以编程强大的TCR-T，并且可以避免IL-21全身利用引起的副作用。新型 IL-21 受体为下一代 TCR-T 对抗 HCC 创造了新的机会。