γδ T 细胞调节小细胞肺癌中的抗肿瘤免疫
γδ T cells modulate anti-tumor immunity in small cell lung cancer.
我们的发现表明，活化的γδ T细胞可能是SCLC治疗的有价值靶点。
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CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
靶向 PD-1 和 CD85j 可恢复瘤内 CD4⁺ GzmB⁺ T 细胞功能以对抗表达 MHC-II 的肿瘤
英文原题：Targeting PD-1 and CD85j can restore intratumoral CD4(+) GzmB(+) T-cell functions to combat MHC-II-expressing tumors.
查看英文原题
Targeting PD-1 and CD85j can restore intratumoral CD4(+) GzmB(+) T-cell functions to combat MHC-II-expressing tumors.
研究概要
我们的研究表明，肿瘤浸润性 CD4⁺GzmB⁺ T 细胞无法清除肿瘤。
中文摘要
背景：已发现一类具有细胞毒活性的 CD4⁺ T 细胞，它们通过表达穿孔素和颗粒酶发挥作用。尽管对多种疾病中的细胞毒性 CD4⁺ T 细胞表征已取得进展，非小细胞肺癌（NSCLC）中的此类细胞现状，以及促进肿瘤内细胞毒性 CD4⁺ T 细胞活化的机制仍不清楚。方法：研究者采用流式细胞术检查 NSCLC 患者外周血和肿瘤组织中 CD4⁺GzmB⁺ T 细胞的表型和功能特性。通过功能缺失分析和 RNA 测序，探究 IL-15 在体外恢复 CD4⁺GzmB⁺ T 细胞功能的机制。使用患者来源肺癌组织离体模型和动物模型，验证免疫检查点抑制剂对 CD4⁺GzmB⁺ T 细胞活化的影响。结果：NSCLC 患者肿瘤浸润、表达颗粒酶 B（GzmB）的 CD4⁺ T 细胞细胞溶解功能受损；IL-15 通过激活 AKT-FOXO1-T-bet 轴恢复该功能。此外，IL-15 以依赖 AKT 的方式提高 CD4⁺GzmB⁺ T 细胞中溶质载体家族 7 成员 5（SLC7A5）的表达；抑制 SLC7A5 会消除 IL-15 对 CD4⁺GzmB⁺ T 细胞的作用。研究还显示，程序性细胞死亡蛋白 1（PD-1）和 CD85j 这两种免疫检查点分子在 CD4⁺GzmB⁺ T 细胞中互斥表达；同时靶向 PD-1 和 CD85j 可通过激活 AKT 通路增强此类细胞的效应功能。值得注意的是，表达主要组织相容性复合体（MHC）II 类分子及 IL-15 的肿瘤细胞，决定免疫治疗应答中 CD4⁺GzmB⁺ T 细胞介导抗肿瘤免疫的效果。结论：本研究表明，肿瘤浸润 CD4⁺GzmB⁺ T 细胞无法清除肿瘤。联合阻断 PD-1 和 CD85j 并给予 IL-15，可恢复这些细胞的效应功能，促进其在肿瘤微环境中转变，从而对抗表达 MHC II 的肿瘤。
展开英文摘要原文
BACKGROUND: 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. METHODS: We used flow cytometry to examine the phenotypic and functional properties of CD4 + GzmB + 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 CD4 + GzmB + 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 CD4 + GzmB + T-cell activation. RESULTS: 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 CD4 + GzmB + T cells in an Protein Kinase B (AKT)-dependent manner, and inhibition of SLC7A5 abrogated the effect of IL-15 on CD4 + GzmB + T cells. Additionally, we showed that the immune checkpoint molecules programmed cell death-1 (PD-1) and CD85j were mutually exclusively expressed in CD4 + GzmB + T cells and that dual targeting of PD-1 and CD85j enhanced the effector function of CD4 + GzmB + T cells by activating the AKT pathway. Notably, tumor cells expressing major histocompatibility complex (MHC)-II and IL-15 determine the effectiveness of CD4 + GzmB + T-cell-mediated antitumor immunity in response to immunotherapy. CONCLUSIONS: Our study demonstrated that tumor-infiltrating CD4 + GzmB + T cells fail to eliminate tumors. Dual blockade of PD-1 and CD85j alongside IL-15 restores the effector function of CD4 + GzmB + T cells and drives CD4 + GzmB + T-cell transformation in the tumor microenvironment to combat MHC-II-expressing tumors.
论文信息
- 作者
- Wang B、Wang X、Wang T、Meng K、Yu T、Xi Y、Hu S、Xiong H
- 第一作者单位
- Department of Thoracic Surgery, Huazhong University of Science and Technology Tongji Medical College Tongji Hospital, Wuhan, Hubei, China.China
- 通讯作者单位
- Department of Thoracic Surgery, Huazhong University of Science and Technology Tongji Medical College Tongji Hospital, Wuhan, Hubei, China lqli@tjh.tjmu.edu.cn fuxn2006@aliyun.com.China
- 期刊
- Journal for immunotherapy of cancer2025 Apr 1
- 原文标识
- PubMed 40169283 · DOI 10.1136/jitc-2024-010890