CELL INTELLIGENCE · 肿瘤细胞治疗研究

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转录因子 ZEB2 介导 TIL（肿瘤浸润淋巴细胞）在非小细胞肺癌中的抗肿瘤疗效

英文原题：The transcription factor ZEB2 mediates the antitumor efficacy of tumor-infiltrating lymphocytes in non-small cell lung cancer.

查看英文原题

The transcription factor ZEB2 mediates the antitumor efficacy of tumor-infiltrating lymphocytes in non-small cell lung cancer.

PubMed 2025/11/07（内容时间） Cell Death Dis Q1 · IF 12.2（JCR 2025）

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非小细胞肺癌地区：中国
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中文摘要

免疫检查点阻断（ICB）为晚期非小细胞肺癌（NSCLC）提供了一种在体内激活CD8+TIL（肿瘤浸润淋巴细胞）（CD8+TILs）的方法。很大一部分NSCLC患者对ICB无应答并复发，原因是出现了细胞毒性受损的功能失调CD8+TILs。

因此，为了NSCLC患者ICB治疗的成功，需要更好地理解有利于细胞毒性T效应细胞而非功能失调CD8+TILs发育的调控因子。

在此，我们基于metaVIPER对来自14例未经治疗的NSCLC患者的深度CD8+细胞scRNA-seq数据进行分析，揭示主调控子ZEB2可能驱动NSCLC肿瘤中CD8+沿细胞毒性效应轨迹分化。在体外，ZEB2作用于T-bet下游，刺激肺肿瘤反应性T效应细胞分化。这一T-bet/ZEB2轴对KP.SIY肺肿瘤表现出独立于ICB治疗的免疫治疗效应，并介导小鼠血清白蛋白融合IL-2+IL-12联合免疫治疗（IL2-MSA+IL12-MSA）在小鼠中的治疗效果。IL2-MSA+IL12-MSA通过平行的STAT4/FOXO1介导机制发挥作用，促进CD8+TIL中T-bet/ZEB2表达及肺肿瘤反应性T效应细胞分化。

总之，支持CD8+细胞中ZEB2活性的免疫治疗方案可能在NSCLC患者中具有前景。

展开英文摘要原文

Immune checkpoint blockade (ICB) offers an in vivo approach to activate CD8 + tumor-infiltrating lymphocytes (CD8 + TILs) in cases of advanced non-small cell lung cancer (NSCLC). A large fraction of NSCLC patients is unresponsive to ICBs and relapse due to the development of dysfunctional CD8 + TILs with impaired cytotoxicity.

Therefore, an improved understanding of regulator(s) that favor the development of cytotoxic T eff cells over dysfunctional CD8 + TILs is required for the success of ICB therapy in NSCLC patients.

Here, our metaVIPER-based scRNA-seq analysis of deep CD8 + cell scRNA-seq data from 14 treatment-na ve NSCLC patients revealed that the master regulon ZEB2 may drive CD8 + differentiation along the cytotoxic effector trajectory in NSCLC tumors. In vitro, ZEB2 acts downstream of T-bet to stimulate lung tumor-reactive T eff cell differentiation. This T-bet/ZEB2 axis displays immunotherapeutic effects on KP.

SIY lung tumors independent of ICB therapy and mediates the therapeutic effects of murine serum albumin-fused IL-2 + IL-12 combination immunotherapy (IL2-MSA + IL12-MSA) in mice. IL2-MSA + IL12-MSA operates through a parallel STAT4/FOXO1-mediated mechanism that promotes CD8 + TIL T-bet/ZEB2 expression and lung tumor-reactive T eff cell differentiation.

In conclusion, immunotherapeutic regimens that support ZEB2 activity in CD8 + cells may show promise in NSCLC patients.

论文信息

作者
Wang J、Liu F、Li Y、Gao J、Yang S、Tian M、Deng L、Yang Y
第一作者单位
Anhui Province Key Laboratory of Respiratory Tumor and Infectious Disease, the Department of Pulmonary Critical Care Medicine, First Affiliated Hospital of Bengbu Medical University, Bengbu, China.China
通讯作者单位
Anhui Province Key Laboratory of Respiratory Tumor and Infectious Disease, the Department of Pulmonary Critical Care Medicine, First Affiliated Hospital of Bengbu Medical University, Bengbu, China. xjwang1975@bbmu.edu.cn.China
期刊
Cell death & disease2025 Nov 7
原文标识
PubMed 41203628　·　DOI 10.1038/s41419-025-08112-y

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