Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3052, Australia; Cambridge Institute for Medical Research, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK.
Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3052, Australia.
Cancer Cell. 2019 Oct 14;36(4):385-401.e8. doi: 10.1016/j.ccell.2019.08.008. Epub 2019 Sep 26.
Loss of MHC class I (MHC-I) antigen presentation in cancer cells can elicit immunotherapy resistance. A genome-wide CRISPR/Cas9 screen identified an evolutionarily conserved function of polycomb repressive complex 2 (PRC2) that mediates coordinated transcriptional silencing of the MHC-I antigen processing pathway (MHC-I APP), promoting evasion of T cell-mediated immunity. MHC-I APP gene promoters in MHC-I low cancers harbor bivalent activating H3K4me3 and repressive H3K27me3 histone modifications, silencing basal MHC-I expression and restricting cytokine-induced upregulation. Bivalent chromatin at MHC-I APP genes is a normal developmental process active in embryonic stem cells and maintained during neural progenitor differentiation. This physiological MHC-I silencing highlights a conserved mechanism by which cancers arising from these primitive tissues exploit PRC2 activity to enable immune evasion.
癌细胞中 MHC I 类抗原呈递的缺失会引发免疫治疗抵抗。全基因组 CRISPR/Cas9 筛选鉴定出多梳抑制复合物 2 (PRC2) 的一个进化保守功能，该功能介导 MHC I 抗原加工途径 (MHC-I APP) 的协调转录沉默，促进 T 细胞介导的免疫逃逸。MHC-I 低表达癌症中的 MHC-I APP 基因启动子含有二价激活的 H3K4me3 和抑制性 H3K27me3 组蛋白修饰，沉默基础 MHC-I 表达并限制细胞因子诱导的上调。MHC-I APP 基因的二价染色质是胚胎干细胞中活跃的正常发育过程，并在神经祖细胞分化过程中维持。这种生理 MHC-I 沉默突出了一个保守机制，即源自这些原始组织的癌症利用 PRC2 活性来实现免疫逃逸。
