纤维细胞生长因子受分子向剂的抑制减轻肝细胞癌中免疫抑制组织微环境
Hiroyuki Suzuki1,2, Hideki Iwamoto3,4,5, Toshimitsu Tanaka6,7
1Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan. suzuki_hiroyuki@med.kurume-u.ac.jp.
Hepatology international
|October 21, 2023
概括
分子向剂 (MTAs) 在晚期肝细胞癌 (HCC) 中影响瘤免疫微环境 (TIME). 伦瓦提尼布和AZD4547通过降低脂质代谢的调节来促进热免疫状态,支持HCC的组合免疫疗法.
科学领域:
- 免疫学 免疫学 免疫学
- 在瘤学瘤学.
- 药理学 药理学是指药理学的学科.
背景情况:
- 使用免疫检查点抑制剂 (ICI) 和分子向剂 (MTA) 的组合免疫疗法已被批准用于晚期肝细胞癌 (HCC).
- 由于单独ICI的抗瘤效果有限 (高达30%),ICI后的连续治疗通常是必要的.
- 了解MTA对瘤免疫微环境 (TIME) 的影响对于优化HCC治疗至关重要.
研究的目的:
- 研究各种分子向剂 (MTA) 对肝细胞癌 (HCC) 瘤免疫微环境 (TIME) 的影响.
- 为了确定MTA是否可以改变时间到一个更免疫活跃的状态.
- 探索人类HCC细胞中观察到的变化的临床相关性.
主要方法:
- 已确立的免疫综合性正型HCC小鼠模型 (Hep-55.1C,Hep-53.4) 并用MTAs (伦瓦提尼布,索拉费尼布,雷戈拉费尼布,卡博桑提尼布,DC101,AZD4547) 治疗两周.
- 评估了使用免疫组织化学检测免疫细胞标记物 (CD3,CD8,Foxp3,NK1.1,F4/80,CD11c) 和免疫检查点分子 (PD-1,PD-L1) 的TIME变化.
- 在lenvatinib和AZD4547治疗的瘤和用lenvatinib治疗的人类HCC细胞 (MHCC-97H) 上进行RNA-seq,以分析基因表达变化,特别是脂质代谢.
主要成果:
- 许多MTA在时间内减少了Foxp3-和F4/80阳性细胞.
- 卡博桑提尼布增加了NK1.1,Granzyme B和CD11c阳性细胞,表明先天免疫系统的激活.
- 伦瓦提尼布和AZD4547增加了CD8,Granzyme B和PD-L1阳性细胞,表明向"热"免疫状态的转变. 基因本体学分析揭示了这些药物对脂质代谢相关基因的下调.
结论:
- 卡博桑提尼布在HCC TIME中激活先天免疫系统.
- 伦瓦替尼和AZD4547,常见的FGFR抑制剂,通过降低脂质代谢相关基因的调节,促进"热"免疫状态.
- 这些发现支持使用伦瓦替尼和AZD4547作为高级HCC的组合免疫疗法.
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