精确准β-catenin诱导瘤重编程和免疫力在肝细胞癌症
Brandon M Lehrich1,2,3, Evan R Delgado2,4, Tyler M Yasaka1,2,3
1Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Research square
|December 23, 2024
概括
一种针对肝细胞癌 (HCC) 中CTNNB1突变的新疗法显示出有前途. 这种治疗重新编程瘤和免疫反应,单独改善结果,并在临床前模型中使用免疫检查点抑制剂 (ICI).
科学领域:
- 肝细胞癌研究 肝细胞癌研究
- 癌症免疫学 癌症免疫学
- 在RNA治疗方面,RNA疗法.
背景情况:
- 具有Wnt活性突变 (CTNNB1,AXIN1/2,APC) 的肝细胞癌 (HCC) 由于排除瘤微环境,往往对免疫检查点抑制剂 (ICI) 的反应有限.
- 针对CTNNB1 (编码β-catenin) 是这些HCC子集的潜在策略.
研究的目的:
- 在β-catenin突变的HCC模型中评估针对CTNNB1 (LNP-CTNNB1) 的新型脂质纳米颗粒封装siRNA的疗效.
- 研究LNP-CTNNB1对瘤微环境和免疫反应的影响.
- 评估LNP-CTNNB1与ICI的协同作用潜力.
主要方法:
- 利用了具有β-catenin突变的多种免疫能力的HCC模型.
- 采用单细胞和空间转录组学来分析细胞和区域变化.
- 评估了免疫调节转录因子 (IRF2,POU2F1),干扰素信号传递和先天性/适应性免疫变化.
- 评估了LNP-CTNNB1作为单疗法和ICI联合治疗晚期疾病的疗效.
- 分析了与阿特佐利祖马布加贝瓦西祖马布治疗反应和存活率相关的淋巴结合的患者数据.
主要成果:
- 在β-catenin突变的HCC模型中,LNP-CTNNB1显示出显著的瘤反应.
- 通过LNP-CTNNB1诱导的细胞和区域重编程抑制β-catenin,激活IRF2和POU2F1.1.
- 观察到干扰素信号的重新启动以及先天性和适应性免疫的改变.
- LNP-CTNNB1与ICI协同作用,增强了晚期疾病中细胞毒性T细胞的招募.
- 在接受治疗的患者中,淋巴细胞总量的减少与改善的反应和生存相关.
结论:
- LNP-CTNNB1作为单一治疗和与ICI联合治疗CTNNB1突变的HCC有效.
- 该疗法影响瘤细胞信号传递,并重塑免疫监测,包括T细胞反应.
- 这些发现为临床研究LNP-CTNNB1在CTNNB1突变的HCC提供了强有力的理由.
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