在肺状细胞癌中,EZH2抑制促进瘤免疫性
Tanner J DuCote1, Xiulong Song1, Kassandra J Naughton1
1Department of Toxicology and Cancer Biology, University of Kentucky, Lexington KY 40536 USA.
bioRxiv : the preprint server for biology
|June 19, 2023
概括
抑制EZH2通过改善抗原呈现和减少免疫抑制来增强肺状细胞癌 (LSCC) 的免疫检查点抑制剂 (ICI) 反应. 这种方法有望提高LSCC患者的治疗疗效.
科学领域:
- 在瘤学瘤学.
- 免疫学 免疫学 免疫学
- 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:
- 肺状细胞癌 (LSCC) 中对免疫检查点抑制剂 (ICI) 的耐药性与免疫抑制微环境和抗原呈现不佳有关.
- 增强Zeste同源2 (EZH2) 是一种甲基转移酶,涉及表观遗传调节和瘤进展.
研究的目的:
- 研究是否抑制EZH2可以克服耐药性并改善LSCC中的ICI反应.
- 阐明EZH2抑制影响瘤微环境和抗原呈现的分子机制.
主要方法:
- 利用了LSCC的2D细胞系,3D器官 (来自小鼠和患者) 和体内模型.
- 用EZH2抑制剂结合干扰素- (IFNγ) 和抗PD1免疫疗法治疗的模型.
- 对MHC类I/II进行了mRNA/蛋白质表达分析,对基因素标记进行了ChIP测序,以及单细胞RNA测序.
主要成果:
- 在mRNA和蛋白质水平上,EZH2抑制对主要基因相容性复合物I和II类 (MHCI/II) 表达进行了上调.
- ChIP测序证实了EZH2介导的抑制性和激活性基因素标记的改变.
- 结合EZH2抑制和抗PD1免疫疗法在LSCC模型中显示出显著的瘤控制,观察到向不太免疫抑制的表型转移.
结论:
- 抑制EZH2可以恢复抗原呈现,并调节LSCC中的瘤免疫微环境.
- 这种治疗策略有可能提高LSCC患者免疫检查点抑制剂的疗效.
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