多种学识别了瘤内在的SREBP1,在肝细胞癌中驱动免疫排除
Rebekah E Dadey1,2, Ruxuan Li1,3, Jake Griner4
1UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA.
Journal for immunotherapy of cancer
|June 15, 2025
概括
固醇调节元素结合蛋白1 (SREBP1) 通过重编程巨细胞,驱动肝癌中的免疫排除. 向SREBP1可以克服对免疫检查点抑制剂 (ICI) 的耐药性,并在肝细胞癌 (HCC) 中增强抗瘤免疫力.
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:
- 免疫检查点抑制剂 (ICI) 在肝细胞癌 (HCC) 中表现有希望,但益处往往有限.
- 标志着免疫细胞透和功能不佳的非T细胞炎症瘤与降低的ICI反应相关.
- 确定新的治疗点对于克服HCC的ICI耐药性至关重要.
研究的目的:
- 为了确定瘤内在驱动器的免疫排除在HCC.
- 研究固醇调节元素结合蛋白1 (SREBP1) 在调节瘤微环境和ICI反应中的作用.
- 探索SREBP1作为一种潜在的治疗点,用于提高HCC中ICI疗效.
主要方法:
- 900多个人类HCC标本和31个单细胞RNA标本的大规模多原子分析 (RNA-seq,蛋白质组学).
- 使用成像质量细胞计 (IMC) 和空间脂管学 (MALDI) 进行组织验证.
- 使用3D共同培养模型进行体外功能测试,以评估CD8+T细胞招募和巨细胞两极分化.
主要成果:
- 发现了32种与免疫排除相关的瘤性途径,其中SREBP1被确定为关键调节者.
- SREBP1信号与增加的脂质生物发生,免疫抑制性巨细胞和减少的CD8+T细胞透相关.
- 在瘤细胞中,CRISPR介导的SREBP1淘汰作用降低了免疫抑制性巨细胞标记物,并在体外增强了CD8+T细胞迁移.
结论:
- 在HCC中,SREBP1是免疫排除的关键驱动因素,部分是通过M2类巨细胞重编程.
- 准SREBP1和相关的脂质生物合成途径提供了一种有希望的策略,以增强抗瘤免疫力.
- 这些发现提名SREBP1作为一种潜在的治疗点,以提高ICI在HCC的疗效.
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