骨髓原体调节失调为瘤中的免疫抑制性巨细胞提供燃料
bioRxiv : the preprint server for biology
|July 9, 2024
概括
肺部瘤重新编程骨髓髓髓原体,以产生免疫抑制性巨细胞. 在这些原始体中准NRF2通路可以减少促进瘤的巨细胞,并增强抗瘤免疫力.
科学领域:
- 免疫学 免疫学 免疫学
- 在瘤学瘤学.
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
背景情况:
- 单细胞衍生巨细胞 (mo-macs) 是瘤微环境 (TME) 中免疫抑制的关键驱动因素.
- 骨髓中瘤诱导的骨髓形成扩大了这些亲瘤起源的骨髓群体.
- 了解骨髓原始体中的调节机制对于向mo-macs.至关重要.
研究的目的:
- 为了确定特定的骨髓原生程序,有助于发展的pro-tumorigenicmo-macs.
- 为了研究Nfe2l2 (NRF2) 途径在TME内的髓状细胞中的作用.
- 评估NRF2作为增强抗瘤免疫力的潜在治疗标.
主要方法:
- 骨髓髓髓质原始体,循环单细胞和瘤透的mo-macs的配对转录组和染色质可访问性分析.
- 对染色质可访问性和基因组修饰的分析.
- 在临床前模型中,NRF2的遗传删除和药理抑制.
主要成果:
- 肺部瘤诱导骨髓髓髓原体NRF2的染色质可访问性,作为对氧化应激的反应.
- 在肺TME中,在单细胞分化为mo-macs期间,NRF2活性保持和上调,促进存活和免疫抑制.
- 抑制NRF2显著降低了mo-mac生存率和免疫抑制功能,增强了NK和T细胞介导的抗瘤免疫力.
结论:
- 该NRF2通路在骨髓原生细胞中是表观遗传原始的,并在mo-macs中持续存在,以支持瘤免疫逃避.
- 向神经髓质原始体中的NRF2代表了克服瘤诱导免疫抑制的可行策略.
- 抑制NRF2与现有的免疫疗法协同作用,例如检查点阻塞,提供新的治疗途径.
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