瘤细胞p38抑制以克服免疫疗法耐药性
Jason J Luke1,2, Rebekah E Dadey1,2, Ryan C Augustin1,2
1Hillman Cancer Center, UPMC, Pittsburgh, PA, USA.
Research square
|August 30, 2023
概括
针对癌细胞中的p38信号传递可以克服对免疫检查点抑制剂 (ICI) 的耐药性. 这种方法通过促进T细胞透来增强抗瘤免疫力,从而改善患者的反应.
科学领域:
- 在瘤学瘤学.
- 免疫学 免疫学 免疫学
- 分子生物学分子生物学
背景情况:
- 许多患有非T细胞炎症瘤的患者由于缺少T细胞和树突细胞激活,对免疫检查点抑制剂 (ICI) 没有反应.
- 了解免疫排除机制对于开发新型组合疗法以改善癌症治疗结果至关重要.
研究的目的:
- 研究瘤细胞p38信号作为治疗点,以增强抗瘤免疫力.
- 为了克服对免疫检查点抑制剂 (ICI) 的耐药性.
主要方法:
- 从头部和部状细胞癌患者的瘤组织的分子分析.
- 全癌症单细胞RNA测序.
- 在癌症细胞系中降低p38.
- 结合ICI的p38抑制的临床前模型.
- 在ICI耐药患者中,p38抑制剂 (pexmetinib) 加上nivolumab的临床试验.
主要成果:
- 在非T细胞炎症瘤中发现了一个以p38为中心的信号网络.
- 瘤细胞p38激活似乎是跨多种癌症类型的免疫排除机制.
- 在临床前模型中,p38抑制增加了T细胞迁移,并且在与ICI结合时显示出更高的疗效.
- 佩克斯美提尼布加尼沃卢马布在不耐PD1/L1治疗的患者中显示出显著的临床反应.
结论:
- 向癌细胞中的p38信号显示出将非T细胞炎症瘤转化为T细胞炎症表型的潜力.
- 抑制p38与抗PD1/PD-L1的联合治疗是克服免疫疗法耐药性和实现持久临床反应的有希望的策略.
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