细胞内K+限制T细胞耗尽,并保持抗瘤功能
bioRxiv : the preprint server for biology
|September 25, 2023
概括
针对瘤微环境,研究人员发现,通过Na+/K+ ATPase删除降低T细胞中的细胞内,矛盾地导致了T细胞耗尽. 这表明仔细的离子运输工程对于有效的癌症免疫治疗至关重要.
科学领域:
- 免疫学 免疫学 免疫学
- 癌症生物学 癌症生物学
- 细胞生理学 细胞生理学
背景情况:
- 瘤微环境经常抑制T细胞活动,阻碍抗癌免疫反应.
- 瘤内细胞外 (K+) 的升高会通过影响Akt-mTOR信号传递,损害CD8+T细胞功能.
- 以前的研究发现,高细胞外K+与瘤中的T细胞抑制有关.
研究的目的:
- 通过基因降低T细胞中的细胞内K+,以克服K+介导的抑制.
- 研究 Na+/K+ ATPase 删除对 CD8+ T 细胞功能和表型的影响.
- 探索细胞内K+水平,ROS积累和T细胞耗尽之间的机制联系.
主要方法:
- 在老鼠和人类CD8+ T细胞中,CRISPR-Cas9介导的Na+/K+ ATPaseα子单元的删除.
- 转录组分析以评估基因表达变化.
- 在小鼠黑色素瘤模型中评估T细胞信号传递,分化,ROS积累,持久性和抗瘤活性.
主要成果:
- 删除Na+/K+ ATPase降低了细胞内K+,但导致了强力信号过活和T细胞耗尽 (TEx) 现型.
- 从机制上讲,Na+/K+ ATPase的破坏导致了由于细胞内K+耗尽而导致反应性氧物种 (ROS) 积累.
- 抗氧化剂治疗或高K+介质阻止了ATp1a1缺乏T细胞中的TEx细胞的形成.
- 缺少Atp1a1的T细胞在体内表现出受损的持久性和抗瘤活性.
结论:
- 通过Na+/K+ ATPase删除来减少细胞内K+的基因减少促进T细胞疲劳,抵消治疗目标.
- 在Na+/K+ ATPase中断后,ROS积累是T细胞耗尽的关键媒介.
- 未来的转化策略必须平衡降低细胞内K + 与缓解瘤特异性T细胞中的ROS积累,以有效的癌症免疫疗法.
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