表达IL-10的CAR-T细胞抵抗功能障碍,并提供固体瘤和转移的持续清除
Yang Zhao1,2, Jiangqing Chen3, Massimo Andreatta4,5
1Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Nature biotechnology
|January 3, 2024
概括
工程化仿真抗原受体 (CAR) T细胞分泌互白素-10 (IL-10) 克服了固体瘤的挑战. 这种代谢装甲方法增强T细胞功能,导致瘤根除和持久免疫力.
科学领域:
- 免疫治疗是一种免疫疗法.
- 在瘤学瘤学.
- 细胞工程 细胞工程
背景情况:
- 化学抗原受体 (CAR) T细胞疗法在血液癌症中表现有前途,但由于T细胞疲劳和功能障碍,在固体瘤中面临挑战.
- 瘤微环境有助于CAR T细胞功能障碍,限制治疗疗效.
- 克服T细胞功能障碍对于扩大CAR T细胞治疗到固体恶性瘤至关重要.
研究的目的:
- 设计CAR-T细胞以抵抗瘤微环境中的功能障碍.
- 为了增强CAR T细胞代谢功能和对固体瘤治疗的效应器能力.
- 评估在临床前癌症模型中代谢装甲的CAR T细胞的疗效.
主要方法:
- 汽车T细胞被设计为分泌互白素-10 (IL-10) 进行代谢装甲.
- 在瘤微环境中的IL-10分泌CAR T细胞中评估了线粒体结构,功能和氧化酸化.
- 在结肠癌,乳腺癌,黑色素瘤和胰腺癌的合成和异种移植小鼠模型中评估了治疗疗效.
主要成果:
- IL-10分泌的CAR T细胞保持了线粒体的完整性,并增强了氧化酸化.
- 改造的CAR T细胞表现出增加的增殖和效应器功能,导致已建立的固体瘤和转移性癌症的完全回归.
- IL-10 CAR T 细胞诱导了持久的,类似干细胞的记忆反应,提供了对瘤复发的保护.
结论:
- 通过IL-10分泌来对CAR-T细胞进行代谢装甲是抵消固体瘤中T细胞功能障碍的可行策略.
- 这种方法带来了强大的抗瘤活性,包括根除既定和转移性癌症.
- 改造的CAR T细胞建立了长期的免疫保护,为固体瘤免疫疗法提供了可通用的平台.
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