瘤中辐射诱导的先天性中性粒细胞反应由CXCLs/CXCR2轴介导
Faya Zhang1, Oscar Mulvaney1, Erica Salcedo1
1Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Cancers
|December 9, 2023
概括
放射治疗 (RT) 通过CXCLs/CXCR2轴触发瘤中的炎症,吸引中性粒细胞. 阻止这种途径模仿中性粒细胞枯竭,抑制瘤生长并改善存活率.
科学领域:
- 免疫学 免疫学 免疫学
- 在瘤学瘤学.
- 辐射疗法 辐射疗法
背景情况:
- 放射治疗 (RT) 在瘤微环境 (TME) 中诱导炎症和免疫调节效应.
- 早期的先天性免疫反应,特别是中性粒细胞透,在RT后至关重要,但潜在的机制尚不清楚.
- 中性粒细胞是对RT的关键早期反应者,在24-48小时内透到瘤中.
研究的目的:
- 阐明TME中RT驱动的早期炎症机制.
- 研究DNA感应通路和CXCLs/CXCR2轴在RT诱导的中性友浸透中的作用.
- 评估RT中准CXCLs/CXCR2轴的治疗潜力.
主要方法:
- 使用了突变性小鼠瘤模型 (RM-9和MC-38).
- 采用了CXCR2阻断和直接中性粒细胞减少策略.
- 分析了CXCLs,cGAS,AIM2和IL-1β的基因和蛋白质表达.
- 进行了mRNA-Seq和基因本体学分析.
主要成果:
- 阻断CXCR2显著降低了RT诱导的中性友入侵TME.
- 在RT诱导的瘤抑制和宿主生存中,CXCR2阻断表现出与中性粒细胞枯竭相似的疗效.
- RT上调了CXCLs并激活了cGAS/AIM2 DNA感应通路,导致IL-1β的产生和随后的CXCLs/CXCR2轴激活.
- 中性粒细胞被确定为免疫细胞中CXCR2的主要表达体.
结论:
- 在TME内,CXCLs/CXCR2轴是RT诱导的先天性炎症的关键媒介.
- 这个轴很可能转换来自RT诱导的DNA损伤激活的先天DNA感应通路的信号.
- 准CXCLs/CXCR2轴是一种有前途的策略,通过调节瘤免疫反应来增强RT疗效.
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