缺氧诱导的EGR1重塑中性粒细胞以抑制抗瘤免疫力
Tian-Gen Chang1, Jay Friedman2, Paul E Clavijo2
1Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Science immunology
|December 12, 2025
概括
早期生长反应蛋白1 (EGR1) 在缺氧下驱动瘤相关中性粒细胞的免疫抑制. 准缺氧-EGR1通路可能会克服对癌症免疫疗法的抗性.
科学领域:
- 免疫学 免疫学 免疫学
- 癌症生物学 癌症生物学
- 分子生物学分子生物学
背景情况:
- 瘤中的中性粒细胞通常表现出免疫抑制特征,但机制尚未完全理解.
- 瘤微环境可以诱导中性粒细胞采用抑制抗瘤免疫反应的表型.
研究的目的:
- 确定瘤中中性粒细胞免疫抑制的关键调节剂.
- 研究早期生长反应蛋白1 (EGR1) 在瘤相关的中性粒细胞功能和免疫抑制中的作用.
主要方法:
- 使用小鼠模型 (野生类型和EGR1缺乏) 调查了中性粒细胞中EGR1的作用.
- 分析了中性粒细胞的核形态和免疫抑制因子表达.
- 在小鼠口腔癌模型中利用收养转移实验.
- 研究了MEK通路抑制对中性粒细胞功能和瘤控制的影响.
- 在中性粒细胞中相关的EGR1表达与癌症患者的临床结果.
主要成果:
- 中性粒细胞中缺氧诱导的EGR1表达改变了核形态,并增强了T细胞抑制.
- 缺乏EGR1的中性粒细胞没有表现出缺氧驱动的免疫抑制变化.
- 野生型中性粒细胞的转移赋予了PD-1封锁的抵抗力,而Egr1-缺乏的中性粒细胞恢复了敏感性.
- 抑制MEK通路减少了中性粒细胞的免疫抑制,并提高了PD-1阻断的有效性.
- 一个EGR1+中性粒细胞签名预测了多种癌症类型的不良结果.
结论:
- EGR1是一种临界的缺氧诱导性转录因子,驱动中性粒细胞介导的瘤免疫抑制.
- 针对缺氧-EGR1轴提供了一个潜在的策略,以提高癌症免疫疗法的疗效.
- EGR1+中性粒细胞作为预后生物标志物,用于诊断不良的临床结果.
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