Melanoma Immunology and Oncology Group, The Centenary Institute, University of Sydney, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia; These authors contributed equally.
Department of Pathology, Dunedin School of Medicine, University of Otago, 270 Great King Street, Dunedin 9054, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, Level, 3A Symonds Street, Auckland, New Zealand; These authors contributed equally.
Trends Immunol. 2019 Apr;40(4):328-344. doi: 10.1016/j.it.2019.02.004. Epub 2019 Mar 7.
Methylation of DNA at CpG sites is the most common and stable of epigenetic changes in cancer. Hypermethylation acts to limit immune checkpoint blockade immunotherapy by inhibiting endogenous interferon responses needed for recognition of cancer cells. By contrast, global hypomethylation results in the expression of programmed death ligand 1 (PD-L1) and inhibitory cytokines, accompanied by epithelial-mesenchymal changes that can contribute to immunosuppression. The drivers of these contrasting methylation states are not well understood. DNA methylation also plays a key role in cytotoxic T cell 'exhaustion' associated with tumor progression. We present an updated exploratory analysis of how DNA methylation may define patient subgroups and can be targeted to develop tailored treatment combinations to help improve patient outcomes.
CpG 位点的 DNA 甲基化是癌症中最常见和最稳定的表观遗传变化。过度甲基化通过抑制识别癌细胞所需的内源性干扰素反应，限制免疫检查点阻断免疫疗法的效果。相比之下，全局低甲基化导致程序性死亡配体 1 (PD-L1) 和抑制性细胞因子的表达，并伴有上皮间质变化，可能导致免疫抑制。这些相反的甲基化状态的驱动因素还不是很清楚。DNA 甲基化在与肿瘤进展相关的细胞毒性 T 细胞“耗竭”中也起着关键作用。我们提出了一个关于 DNA 甲基化如何定义患者亚群以及如何靶向治疗以帮助改善患者预后的更新探索性分析。
