Yan Hui, Dai Yulin, Zhang Xiaolong, Zhang Hedong, Xiao Xiang, Fu Jinfei, Zou Dawei, Yu Anze, Jiang Tao, Li Xian C, Zhao Zhongming, Chen Wenhao
Immunobiology & Transplant Science Center, Department of Surgery, Houston Methodist Research Institute & Institute for Academic Medicine, Houston Methodist Hospital, Houston, TX 77030, USA.
Department of Medicine Oncology, The General Hospital of Ningxia Medical University, Yinchuan 750004, China.
iScience. 2023 Sep 28;26(11):108087. doi: 10.1016/j.isci.2023.108087. eCollection 2023 Nov 17.
Understanding the factors that regulate T cell infiltration and functional states in solid tumors is crucial for advancing cancer immunotherapies. Here, we discovered that the expression of interferon regulatory factor 4 (IRF4) was a critical T cell intrinsic requirement for effective anti-tumor immunity. Mice with T-cell-specific ablation of IRF4 showed significantly reduced T cell tumor infiltration and function, resulting in accelerated growth of subcutaneous syngeneic tumors and allowing the growth of allogeneic tumors. Additionally, engineered overexpression of IRF4 in anti-tumor CD8 T cells that were adoptively transferred significantly promoted their tumor infiltration and transition from a naive/memory-like cell state into effector T cell states. As a result, IRF4-engineered anti-tumor T cells exhibited significantly improved anti-tumor efficacy, and inhibited tumor growth either alone or in combination with PD-L1 blockade. These findings identify IRF4 as a crucial cell-intrinsic driver of T cell infiltration and function in tumors, emphasizing the potential of IRF4-engineering as an immunotherapeutic approach.
了解调节实体瘤中T细胞浸润和功能状态的因素对于推进癌症免疫疗法至关重要。在此，我们发现干扰素调节因子4（IRF4）的表达是有效的抗肿瘤免疫的关键T细胞内在需求。IRF4基因在T细胞中特异性敲除的小鼠表现出T细胞肿瘤浸润和功能显著降低，导致皮下同基因肿瘤生长加速，并允许异基因肿瘤生长。此外，在过继转移的抗肿瘤CD8 T细胞中通过基因工程过表达IRF4，显著促进了它们的肿瘤浸润以及从幼稚/记忆样细胞状态向效应T细胞状态的转变。结果，经IRF4基因工程改造的抗肿瘤T细胞表现出显著提高的抗肿瘤功效，并且单独或与PD-L1阻断联合使用时均能抑制肿瘤生长。这些发现确定IRF4是肿瘤中T细胞浸润和功能的关键细胞内在驱动因素，强调了IRF4基因工程作为一种免疫治疗方法的潜力。
