在固体瘤中,NR4A转录因子限制了CAR T细胞功能
Joyce Chen1,2,3,4, Isaac F López-Moyado5,6,7, Hyungseok Seo5
1Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA, USA. jchen@lji.org.
Nature
|March 1, 2019
概括
由于NR4A转录因子,针对固体瘤的化学抗原受体 (CAR) T细胞变得功能障碍. 抑制这些NR4A因子可以恢复CAR- T细胞功能,从而改善癌症免疫疗法.
科学领域:
- 免疫学
- 癌症生物学
- 分子生物学
背景情况:
- 化学抗原受体 (CAR) T 细胞对B细胞恶性瘤有效,但对固体瘤效果较差.
- 固体瘤中CAR T细胞功能障碍与慢性抗原刺激和抑制受体的上调有关.
- 这种低反应状态涉及特定的转录因子激活通路.
研究的目的:
- 研究固体瘤中CAR T细胞低反应的机制.
- 确定参与CAR T细胞功能障碍的关键分子参与者.
- 探索用于增强癌症T细胞免疫疗法的新疗法目标.
主要方法:
- 将人类的CD19反应性CAR T细胞转移到CD19+瘤携带的小鼠模型中.
- 对瘤透性淋巴细胞 (TIL) 的基因表达和染色质可访问性的分析.
- 产生和评估NR4A转录因子三重淘汰CAR T细胞.
主要成果:
- 瘤中的CD8+CAR T细胞和内源性TILs表现出与NR4A转录因子相关的相似基因表达特征.
- 在癌症患者和慢性感染患者的T细胞中,NR4A转录因子的表达很高.
- NR4A三重淘汰赛CAR T细胞促进瘤回归,延长存活时间,并表现出效应T细胞表型.
结论:
- NR4A转录因子在T细胞低反应性中起着关键的细胞内在作用.
- 抑制NR4A是克服癌症T细胞功能障碍的一个有希望的策略.
- 向NR4A因子可以提高CAR T细胞治疗固体瘤的疗效.
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