酸性诱导Treg细胞抑制功能的持久增强,用于瘤免疫逃避
Nikita L Mani1, Samuel E Weinberg1, Shuvam Chaudhuri2
1Department of Pathology, Northwestern University, USA; Center for Human Immunobiology, Northwestern University, USA.
Molecular immunology
|August 30, 2024
概括
瘤酸度通过重编程新陈代谢来增强调节性T (Treg) 细胞免疫抑制,但添加乳酸会逆转这种效应. 这种酸性诱导的Treg增强促进瘤生长和免疫逃避.
科学领域:
- 免疫学 免疫学 免疫学
- 癌症生物学 癌症生物学
- 代谢调节 代谢调节 代谢调节
背景情况:
- 瘤微环境 (TME) 由于代谢失调,如乳酸生产增加,往往是酸性.
- 调节性T (Treg) 细胞对于瘤中的免疫逃避至关重要.
- 酸度在Treg细胞功能和TME内的适应性中的特定作用仍然在很大程度上未被探索.
研究的目的:
- 调查酸度对Treg细胞功能的影响,并确定潜在的分子机制.
- 探索酸度,乳酸盐和Treg细胞介导的免疫抑制之间的相互作用.
- 为了确定酸性诱导的Treg细胞增强是否持续并影响抗瘤免疫力.
主要方法:
- 用酸性条件和/或乳酸盐对自然Treg (nTreg) 和诱导Treg (iTreg) 细胞进行处理.
- 对Treg细胞表面标记物 (FoxP3,CD25,CTLA4,GITR) 和免疫抑制功能的分析.
- 代谢流量分析,包括线粒体呼吸和糖解.
- 全基因组转录组和代谢学分析.
- 使用小鼠模型进行体内研究,以评估瘤生长和免疫细胞透.
主要成果:
- 酸度显著增强了nTreg细胞的免疫抑制功能,但不是iTreg细胞,而没有改变关键的表面标记物.
- 添加乳酸盐取消了因酸度引起的 nTreg 抑制功能的增强.
- 酸性增加了nTreg细胞中的线粒体呼吸,改变了单碳叶酸代谢,降低了SAM,叶酸和谷氨水平.
- 一个碳代谢物甲酸盐减少了酸性诱导的Treg增强,而SAM和谷氨没有.
- 过渡性体外酸性治疗导致持续的Treg细胞增强,促进体内瘤生长,并减少CD8+T细胞的频率和大酶B的产生.
结论:
- 瘤酸性重编程nTreg细胞代谢,增强其免疫抑制能力并促进瘤免疫逃避.
- 一碳叶酸途径是nTreg细胞中酸度的关键代谢标.
- 酸度介导的Treg细胞增强是持续的,并有助于抑制瘤微环境,突出潜在的治疗点.
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