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重新编程与瘤相关的巨细胞以超越癌细胞
Xian Zhang1, Shun Li1, Isha Malik1
1Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Nature
|June 28, 2023
概括
改变饮食可以重新编程免疫细胞来对抗癌症. 低蛋白饮食会激活与瘤相关的巨细胞 (TAMs),使它们能够通过抑制mTORC1信号来超越MYC过度表达的癌细胞,从而揭示出一种新的免疫抑制途径.
科学领域:
- 免疫学
- 癌症生物学
- 代谢过程
背景情况:
- 细胞竞争是甲状动物的质量控制机制,但可以被癌细胞选择.
- 瘤微环境涉及癌细胞和肌体,如瘤相关的巨细胞 (TAM).
- 影响癌细胞竞争的环境因素尚不清楚.
研究的目的:
- 研究环境因素,特别是饮食如何影响癌细胞的竞争.
- 确定TAM在癌细胞竞争中的作用.
- 确定抑制癌症的新疗法目标.
主要方法:
- 使用MYC过度表达细胞的小鼠模型.
- 操纵饮食中的蛋白质水平 (低蛋白与正常蛋白质饮食).
- 基因改造的TAM可以耗尽关键信号蛋白 (GATOR1,FLCN,Rag GTPases,PIKfyve).
- 评估了mTORC1信号,TFEB/TFE3激活以及瘤生长动态.
主要成果:
- MYC过度表达产生了依赖mTORC1的"获胜者"癌细胞状态.
- 低蛋白饮食抑制了癌细胞mTORC1,但激活了TAMs的TFEB,TFE3和mTORC1,从而减少了瘤的生长.
- 在TAM中减少GATOR1阻断了低蛋白饮食诱导的抑制;在正常饮食中减少FLCN或Rag GTPase模仿了这种抑制.
- 在TAM和癌细胞中,PIKfyve调解了mTORC1的过度激活,影响了竞争力.
结论:
- 可以通过饮食重新编程TAM来战胜癌细胞.
- 在TAM中非正规的,吞介导的,Rag GTPase独立的mTORC1信号控制细胞间竞争.
- 这是一个具有治疗潜力的新型免疫瘤抑制途径.
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