诱导铁灭可以通过HIF-1α/PD-L1调制增强NSCLC中抗PD-1疗效
Zimin Wang1, Hao Liu2, Jiawei Liang1
1Department of Thoracic Surgery, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Linhai 317000, China; Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Linhai 317000, China.
将铁致死诱导剂与抗PD-1抗体结合起来,可以增强非小细胞肺癌 (NSCLC) 免疫疗法. 这种策略通过阻断PD-L1通路来克服免疫逃避,提高治疗效率.
科学领域:
- 在瘤学瘤学.
- 免疫治疗是一种免疫疗法.
- 癌细胞死亡机制 癌细胞死亡机制
背景情况:
- 免疫检查点抑制剂 (ICI) 在非小细胞肺癌 (NSCLC) 中显示出有限的疗效.
- 铁,一种依赖于铁的细胞死亡,是一种潜在的免疫疗法辅助剂.
- 具有悖论意义的说法是,铁灭诱导剂可以通过对低氧诱导因子1α (HIF-1α) 和编程死亡连接体1 (PD-L1) 的上调来增加瘤免疫逃避.
研究的目的:
- 研究NSCLC免疫疗法中铁亡的分子机制.
- 评估结合铁灭诱导剂与ICI的疗效,以克服治疗的局限性.
主要方法:
- 对162名接受免疫治疗的NSCLC患者的回顾性分析.
- 使用NSCLC细胞系进行体外研究,以评估ferroptosis诱导剂对细胞活力,ROS,PD-L1和HIF-1α的影响.
- 使用小鼠模型进行体内研究,以评估铁致死诱导剂与抗PD-1抗体相结合的治疗效果.
- 染色体免疫沉 (ChIP) 证实HIF-1α与PD-L1促进体结合.
主要成果:
- 在接受免疫治疗的NSCLC患者中,高PD-L1表达与更长的无进展生存 (PFS) 相相关.
- 铁灭诱导剂 (Erastin,RSL3) 诱导细胞死亡,ROS和PD-L1上调,这些被铁化剂逆转.
- 结合IKE和抗PD-1疗法显著抑制瘤生长,并在体内增加CD8+T细胞透.
- 埃拉斯通过PI3K-AKT上调调节HIF-1α,导致PD-L1促进体结合,这种过程被铁化剂逆转.
结论:
- 铁灭诱导剂在NSCLC中表现出双重作用:促进细胞死亡,但也通过PI3K-AKT-HIF-1α-PD-L1通路促进免疫逃避.
- 将铁灭菌诱导剂与抗PD-1抗体结合在一起,可以保持抗瘤效果,克服免疫逃避.
- 这种组合策略提供了一种新的方法来提高NSCLC免疫疗法的疗效.
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