Chatterjee Aniruddha, Rodger Euan J, Ahn Antonio, Stockwell Peter A, Parry Matthew, Motwani Jyoti, Gallagher Stuart J, Shklovskaya Elena, Tiffen Jessamy, Eccles Michael R, Hersey Peter
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 2, 3A Symonds Street, Auckland, New Zealand.
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 2, 3A Symonds Street, Auckland, New Zealand.
iScience. 2018 Jun 29;4:312-325. doi: 10.1016/j.isci.2018.05.021. Epub 2018 Jun 28.
Constitutive expression of the immune checkpoint, PD-L1, inhibits anti-tumor immune responses in cancer, although the factors involved in PD-L1 regulation are poorly understood. Here we show that loss of global DNA methylation, particularly in intergenic regions and repeat elements, is associated with constitutive (PD-L1), versus inducible (PD-L1), PD-L1 expression in melanoma cell lines. We further show this is accompanied by transcriptomic up-regulation. De novo epigenetic regulators (e.g., DNMT3A) are strongly correlated with PD-L1 expression and methylome status. Accordingly, decitabine-mediated inhibition of global methylation in melanoma cells leads to increased PD-L1 expression. Moreover, viral mimicry and immune response genes are highly expressed in lymphocyte-negative plus PD-L1-positive melanomas, versus PD-L1-negative melanomas in The Cancer Genome Atlas (TCGA). In summary, using integrated genomic analysis we identified that global DNA methylation influences PD-L1 expression in melanoma, and hence melanoma's ability to evade anti-tumor immune responses. These results have implications for combining epigenetic therapy with immunotherapy.
免疫检查点蛋白PD-L1的组成性表达会抑制癌症中的抗肿瘤免疫反应，尽管目前对参与PD-L1调控的因素了解甚少。在此我们表明，全基因组DNA甲基化的缺失，尤其是基因间区域和重复元件中的缺失，与黑色素瘤细胞系中组成性（PD-L1）而非诱导性（PD-L1）的PD-L1表达相关。我们进一步表明，这伴随着转录组的上调。从头表观遗传调节因子（如DNMT3A）与PD-L1表达和甲基化组状态密切相关。因此，地西他滨介导的黑色素瘤细胞全基因组甲基化抑制会导致PD-L1表达增加。此外，在癌症基因组图谱（TCGA）中，与PD-L1阴性黑色素瘤相比，病毒模拟和免疫反应基因在淋巴细胞阴性加PD-L1阳性黑色素瘤中高度表达。总之，通过综合基因组分析，我们发现全基因组DNA甲基化会影响黑色素瘤中PD-L1的表达，进而影响黑色素瘤逃避抗肿瘤免疫反应的能力。这些结果对将表观遗传疗法与免疫疗法联合应用具有启示意义。
