失去PHF8会通过激活内源逆转移子诱导病毒模仿反应
Yanan Liu1, Longmiao Hu1, Zhengzhen Wu1
1Shanghai Key Laboratory of Regulatory Biology and School of Life Sciences, East China Normal University, Shanghai, China.
Nature communications
|July 15, 2023
概括
PHD手指蛋白8 (PHF8) 是结肠直肠癌中免疫逃逸的关键驱动因素. 准PHF8会触发病毒模仿反应,增强抗瘤免疫力,改善对免疫检查点阻塞疗法的反应.
科学领域:
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
- 癌症免疫学 癌症免疫学
- 分子生物学分子生物学
背景情况:
- 免疫疗法,包括免疫检查点阻塞 (ICB),是结直肠癌的重要治疗方法.
- 需要新的治疗点来增强抗瘤免疫力并克服对ICB的耐药性.
- PHD手指蛋白8 (PHF8) 是一种参与表观遗传调节的基因组脱甲基酶.
研究的目的:
- 为了研究PHF8在结直肠癌免疫逃生中的作用.
- 确定针对PHF8是否可以增强抗瘤免疫力和ICB疗效.
- 阐明PHF8影响瘤微环境的机制.
主要方法:
- 使用大肠直肠癌的小鼠模型与PHF8切除.
- 评估瘤生长,抗瘤免疫记忆,以及对ICB治疗的反应.
- 研究PHF8对病毒模拟,核酸感知通路和表观遗传修饰 (H3K9me3,SETDB1) 的影响.
- 在人类结直肠腺癌组织中分析PHF8表达.
主要成果:
- 在小鼠模型中,PHF8切除显著抑制了瘤生长,并激活了抗瘤免疫记忆.
- 删除PHF8诱导病毒模仿反应,增加了对ICB治疗的敏感性.
- 通过SETDB1降解,PHF8抑制导致H3K9me3依赖的逆转移素通过SETDB1降解被激活.
- 在人类结直肠癌中,PHF8表达与免疫特征和抗病毒反应相反相关.
结论:
- PHF8作为一个表观遗传检查点,在结直肠癌中调解免疫逃生.
- 准PHF8是一个有希望的策略,可以诱导病毒模仿,增强内在的抗瘤免疫力,并克服ICB耐药性.
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