Wang Boyu, Wang Xu, Wang Tianlai, Meng Kelin, Yu Taiyan, Xi Yu, Hu Shaojie, Xiong Hui, Qu Rirong, Yuan Zhiwei, Wang Xue, Zeng Chenxi, Zou Wenbin, Tian Yitao, Cai Yixin, Fu Shengling, Fu Xiangning, Li Lequn
Department of Thoracic Surgery, Huazhong University of Science and Technology Tongji Medical College Tongji Hospital, Wuhan, Hubei, China.
Department of Thoracic Surgery, Huazhong University of Science and Technology Tongji Medical College Tongji Hospital, Wuhan, Hubei, China
J Immunother Cancer. 2025 Apr 1;13(4):e010890. doi: 10.1136/jitc-2024-010890.
A subset of CD4 T cells with cytotoxic activity has been identified, and these cells exert their effects by expressing perforin and granzymes. Despite the progress made in characterizing cytotoxic CD4 T cells in various diseases, the status of cytotoxic CD4 T cells in non-small cell lung cancer (NSCLC) and the underlying mechanisms involved in promoting intratumoral cytotoxic CD4 T-cell activation remain unclear.
We used flow cytometry to examine the phenotypic and functional properties of CD4GzmB T cells in the peripheral blood and tumor tissues of patients with NSCLC. Loss-of-function analyses and RNA sequencing were used to identify the underlying mechanisms involved in the effects of interleukin (IL)-15 on the restoration of CD4GzmB T-cell function in vitro. A patient-derived lung cancer explant model and an animal model were used to verify the effects of immune checkpoint inhibitors on CD4GzmB T-cell activation.
In patients with NSCLC, impaired cytolytic function of tumor-infiltrated granzyme B (GzmB)-expressing CD4 T cells was restored by IL-15 through activation of the AKT-FOXO1-T-bet axis. Moreover, IL-15 stimulation increased solute carrier family 7 member 5 (SLC7A5) expression in CD4GzmB T cells in an Protein Kinase B (AKT)-dependent manner, and inhibition of SLC7A5 abrogated the effect of IL-15 on CD4GzmB T cells. Additionally, we showed that the immune checkpoint molecules programmed cell death-1 (PD-1) and CD85j were mutually exclusively expressed in CD4GzmB T cells and that dual targeting of PD-1 and CD85j enhanced the effector function of CD4GzmB T cells by activating the AKT pathway. Notably, tumor cells expressing major histocompatibility complex (MHC)-II and IL-15 determine the effectiveness of CD4GzmB T-cell-mediated antitumor immunity in response to immunotherapy.
Our study demonstrated that tumor-infiltrating CD4GzmB T cells fail to eliminate tumors. Dual blockade of PD-1 and CD85j alongside IL-15 restores the effector function of CD4GzmB T cells and drives CD4GzmB T-cell transformation in the tumor microenvironment to combat MHC-II-expressing tumors.
已鉴定出具有细胞毒性活性的CD4 T细胞亚群，这些细胞通过表达穿孔素和颗粒酶发挥作用。尽管在各种疾病中对细胞毒性CD4 T细胞进行表征方面取得了进展，但非小细胞肺癌（NSCLC）中细胞毒性CD4 T细胞的状态以及促进肿瘤内细胞毒性CD4 T细胞活化的潜在机制仍不清楚。
我们使用流式细胞术检测NSCLC患者外周血和肿瘤组织中CD4GzmB T细胞的表型和功能特性。功能丧失分析和RNA测序用于确定白细胞介素（IL）-15对体外CD4GzmB T细胞功能恢复作用的潜在机制。使用患者来源的肺癌外植体模型和动物模型来验证免疫检查点抑制剂对CD4GzmB T细胞活化的影响。
在NSCLC患者中，IL-15通过激活AKT-FOXO1-T-bet轴恢复了肿瘤浸润的表达颗粒酶B（GzmB）的CD4 T细胞受损的溶细胞功能。此外，IL-15刺激以蛋白激酶B（AKT）依赖性方式增加CD4GzmB T细胞中溶质载体家族7成员5（SLC7A5）的表达，并且抑制SLC7A5消除了IL-15对CD4GzmB T细胞的作用。此外，我们表明免疫检查点分子程序性细胞死亡蛋白1（PD-1）和CD85j在CD4GzmB T细胞中相互排斥表达，并且对PD-1和CD85j的双重靶向通过激活AKT途径增强了CD4GzmB T细胞的效应器功能。值得注意的是，表达主要组织相容性复合体（MHC）-II和IL-15的肿瘤细胞决定了CD4GzmB T细胞介导的抗肿瘤免疫对免疫治疗反应的有效性。
我们的研究表明，肿瘤浸润的CD4GzmB T细胞无法消除肿瘤。PD-1和CD85j与IL-15的双重阻断恢复了CD4GzmB T细胞的效应器功能，并在肿瘤微环境中驱动CD4GzmB T细胞转化以对抗表达MHC-II的肿瘤。
