在BAP1无活化的瘤中,SPP1+中性粒细胞介导免疫检查点阻断的抵抗
Jiahao Shi1,2, Shiyun Huang1,2, Yixiong Zhou1,2
1Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Cancer research
|September 12, 2025
概括
瘤抑制剂BAP1的损失通过增加免疫抑制性中性粒细胞来促进癌症免疫逃避. 用抑制剂向CCL2-CCR2通路可以克服这种抵抗免疫检查点阻塞疗法.
科学领域:
- 在瘤学瘤学.
- 免疫学 免疫学 免疫学
- 癌症研究 癌症研究
背景情况:
- BAP1的失活与免疫检查点阻塞 (ICB) 治疗的耐药性和各种癌症的不良结果有关.
- 了解BAP1在瘤微环境中的作用对于开发提高ICB疗效的策略至关重要.
研究的目的:
- 阐明BAP1无活化导致ICB抗性的机制.
- 确定潜在的治疗点,以克服与BAP1相关的ICB耐药性.
主要方法:
- 来自ICB治疗患者的瘤的单细胞转录组分析.
- 在体内研究涉及中性粒细胞和巨细胞枯竭.
- 研究化学激素信号通路,包括CCL2-CCR2轴.
主要成果:
- BAP1的失活促进了免疫抑制性瘤微环境,增加了M2类巨细胞和中性粒细胞.
- 扩大SPP1+中性粒细胞,通过与细胞毒性T细胞相互作用,使其对抗PD-1疗法产生抵抗力.
- BAP1的损失增加了CCL2的分泌,推动了SPP1+中性粒细胞的两极分化和延迟了细胞亡,从而促进了ICB的耐药性.
- 中性粒细胞的枯竭,但不是巨细胞的枯竭,恢复了ICB的敏感性.
结论:
- 通过CCL2介导的SPP1+中性粒细胞两极化,BAP1无活化驱动ICB抵抗.
- 针对CCL2-CCR2轴是一个有希望的策略,以克服在BAP1无活化的瘤中ICB抵抗.
- 调节中性粒细胞功能是恢复BAP1损失背景下的抗瘤免疫力的关键.
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