通过LARP4介导的超翻译驱动了瘤中的T细胞功能障碍
Yi Liu1,2, Haochen Ni3,4,5, Jie Li3,4
1Institute for Immunology, Tsinghua University, Beijing, China.
Nature immunology
|July 22, 2025
概括
针对固体瘤的采用T细胞治疗面临着挑战. 这项研究表明,蛋白质LARP4通过改变翻译来驱动T细胞功能障碍,影响抗瘤反应.
科学领域:
- 免疫学 免疫学 免疫学
- 分子生物学分子生物学
- 癌症研究 癌症研究
背景情况:
- 采用T细胞疗法对固体瘤有前途,但由于T细胞功能障碍和持久性不佳而受到限制.
- 内T细胞表现出转化体重塑,进入与获得的功能障碍相关的超转化状态.
研究的目的:
- 研究RNA结合蛋白LARP4在瘤微环境中的T细胞功能障碍中的作用.
- 确定是否针对LARP4可以提高采用T细胞疗法的疗效.
主要方法:
- 在内T细胞中转化体重塑的分析.
- 研究LARP4在调节mRNA翻译中的功能,特别是氧化酸化 (OXPHOS) 组件.
- 利用Larp4在瘤特异性CD8+T细胞中的淘汰模型和在仿真抗原受体T细胞中的淘汰.
主要成果:
- 在耗尽的T细胞中,LARP4选择性地增强了核编码的OXPHOSmRNA的翻译,导致子单元平衡受损和线粒体功能障碍.
- 在CD8+T细胞中Larp4淘汰减少了超翻译,恢复了线粒体功能,减轻了疲劳,并改善了抗瘤反应.
- 在CAR T细胞中LARP4的淘汰阻止了终端疲劳,并增强了对液体和固体瘤的治疗反应.
结论:
- 由LARP4调节的翻译失调是固体瘤T细胞功能障碍的关键决定因素.
- 针对LARP4是一个潜在的策略,可以提高采用T细胞疗法的长期疗效和持续性.
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