向美酸盐或Wnt通路,以克服TP53突变AML细胞中的CAR T细胞耐药性
Jan Mueller1, Roman R Schimmer1, Christian Koch1
1Department of Medical Oncology and Hematology, University of Zurich and University Hospital Zurich, Zurich, Switzerland.
EMBO molecular medicine
|February 14, 2024
概括
TP53-突变性急性髓性白血病 (AML) 和骨髓囊性瘤 (MDS) 抵抗CAR T细胞治疗. 针对AML细胞中的美酸盐路径或CAR T细胞中的Wnt路径可以克服这种抵抗.
科学领域:
- 免疫学 免疫学 免疫学
- 在瘤学瘤学.
- 细胞生物学 细胞生物学
背景情况:
- 由于抗化疗性,TP53-突变性急性髓性白血病 (AML) 和骨髓囊性瘤 (MDS) 难以治疗.
- 化学抗原受体 (CAR) T细胞对治疗这些疾病有前途,但它们对TP53缺乏性白血病的疗效尚不清楚.
研究的目的:
- 调查AML细胞中TP53缺乏对CAR T细胞疗效的影响.
- 确定涉及TP53缺陷AML对CAR T细胞耐药性的分子途径.
- 探索治疗策略,以加强对TP53-突变AML/MDS的CAR T细胞疗法.
主要方法:
- 在体外和体内研究比较CAR T细胞相互作用与TP53缺乏与野生型AML细胞.
- 对AML细胞和CAR T细胞进行转录分析.
- 在体外验证向美酸盐和Wnt通路的有效性.
主要成果:
- 卡尔T细胞显示了长时间的相互作用,增加了疲劳标记,并减少了TP53缺乏的AML细胞的杀死.
- 缺乏TP53的AML细胞在接触时调节了美酸盐路径,而CAR T细胞在接触时调节了Wnt路径.
- 准AML细胞中的美酸途径或CAR T细胞中的Wnt途径恢复了对CAR T细胞中介杀死的敏感性.
结论:
- 在AML中TP53缺陷使得对CAR T细胞治疗产生抵抗力.
- 梅瓦酸途径在TP53缺乏的AML细胞中代表了治疗的脆弱性.
- Wnt通路调节提供了一种策略,以增强对TP53缺乏AML/MDS的CAR T细胞疗法.
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