癌细胞通过脂肪酸结合蛋白来避免免疫细胞诱导的铁亡
Maria Angelica Freitas-Cortez1,2,3, Fatemeh Masrorpour4, Hong Jiang4
1Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, 75235, USA. mariaangelica.cortez@utsouthwestern.edu.
Molecular cancer
|February 3, 2025
概括
癌细胞通过高调节脂肪酸结合蛋白7 (Fabp7) 来逃避免疫介导的铁和免疫疗法耐药性. 这种蛋白质重编程新陈代谢并破坏免疫细胞功能,促进瘤的存活.
科学领域:
- 免疫学 免疫学 免疫学
- 癌症生物学 癌症生物学
- 代谢途径 代谢途径
背景情况:
- 癌症建立了一个免疫抑制的瘤微环境,阻碍了抗瘤免疫反应.
- CD8+ T 细胞通过脂质过氧化诱导瘤细胞中的铁灭,一种细胞死亡形式,涉及诸如 lysophosphatidylcholine acyltransferase 3 (Lpcat3) 等酶的脂质过氧化.
- 癌细胞逃避免疫疗法诱导的铁亡的机制尚不完全理解.
研究的目的:
- 阐明癌细胞抵抗免疫细胞诱导的铁亡的机制.
- 研究脂肪酸结合蛋白7 (Fabp7) 在癌细胞逃避抗瘤免疫和铁亡中的作用.
主要方法:
- 利用了各种细胞系 (PD1敏感,PD1耐药,B16F10,QPP7质母细胞瘤) 和小鼠模型 (同基因, CD8+ T 细胞中对 Rora 的条件淘汰).
- 采用的技术包括脂管学 (质谱学,有针对性,无针对性),海马分析,qPCR,免疫组织化学,ChIP-seq,ATAC-seq,RNA-seq,西部斑点,共免疫沉,流细胞计和成像质细胞计.
- 在共同培养和体内环境中评估了脂质过氧化,活性氧物种 (ROS) 生成,线粒体功能和T细胞亡.
主要成果:
- 在PD1-耐药瘤中Fabp7的升级促进了代谢适应,从而产生对铁亡和免疫逃避的抵抗力.
- Fabp7在表观遗传上重新编程基因转录,减少铁灭诱导物 (例如Lpcat3) 和增加保护基因 (例如Bmal1).
- 通过增加甘油三和单不和脂肪酸 (MUFA),阻止脂质过氧化和ROS,改善线粒体脂肪酸氧化 (FAO),Fabp7提高瘤细胞生存率.
- 癌细胞在CD8+T细胞中增加Fabp7,扰乱其昼夜钟,通过p53稳定导致亡.
- 临床数据显示,在接受免疫治疗的患者中,更高的FABP7表达与较差的生存结果相关.
结论:
- 癌细胞通过Fabp7上调调节来逃避免疫介导的铁和免疫疗法,Fabp7上调调节重编程脂质代谢并破坏免疫细胞的昼夜调节.
- 向Fabp7是一个潜在的策略,可以使耐铁灭的瘤重新敏感,并提高免疫治疗的疗效.
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