PD-L1 (programmed cell death 1 ligand 1) expression in melanoma has been associated with a better response to anti-PD-1 (programmed cell death 1) therapy. However, patients with PD-L1-negative melanomas can respond to anti-PD-1 blockade, suggesting that the other PD-1 ligand, PD-L2 (programmed cell death 1 ligand 2), might also be relevant for efficacy of PD-1 inhibition. We investigated PD-L2 expression and methylation as a prognostic and predictive biomarker in melanoma. DNA methylation at five CpG loci and gene expression of PD-L2 were evaluated with regard to survival in 470 melanomas from The Cancer Genome Atlas. PD-L2 promoter methylation in correlation with PD-L2 mRNA and protein expression was analyzed in human melanoma cell lines. Prognostic and predictive value of PD-L2 methylation was validated using quantitative methylation-specific PCR in a multicenter cohort of 129 melanoma patients receiving anti-PD-1 therapy. mRNA sequencing data of 121 melanoma patients receiving anti-PD-1 therapy provided by Liu et al. were analyzed for PD-L2 mRNA expression. We found significant correlations between PD-L2 methylation and mRNA expression levels in melanoma tissues and cell lines. Interferon-γ inducible PD-L2 protein expression correlated with PD-L2 promoter methylation in melanoma cells. PD-L2 DNA promoter hypomethylation and high mRNA expression were found to be strong predictors of prolonged overall survival. In pre-treatment melanoma samples from patients receiving anti-PD-1 therapy, low PD-L2 DNA methylation and high PD-L2 mRNA expression predicted longer progression-free survival. PD-L2 expression seems to be regulated via DNA promoter methylation. PD-L2 DNA methylation and mRNA expression may predict progression-free survival in melanoma patients receiving anti-PD-1 immunotherapy. Assessment of PD-L2 should be included in further clinical trials with anti-PD-1 antibodies.

中文翻译：

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黑色素瘤中PD-L2 DNA甲基化和mRNA表达的预后和预测价值。

黑色素瘤中 PD-L1（程序性细胞死亡 1 配体 1）的表达与抗 PD-1（程序性细胞死亡 1）疗法的更好反应有关。然而，PD-L1 阴性黑色素瘤患者可以对抗 PD-1 阻断剂产生反应，这表明另一种 PD-1 配体 PD-L2（程序性细胞死亡 1 配体 2）也可能与 PD-1 的疗效相关。 1 抑制。我们研究了 PD-L2 表达和甲基化作为黑色素瘤预后和预测生物标志物。在来自癌症基因组图谱的 470 个黑色素瘤中，评估了五个 CpG 基因座的 DNA 甲基化和 PD-L2 的基因表达。在人黑色素瘤细胞系中分析了与 PD-L2 mRNA 和蛋白质表达相关的 PD-L2 启动子甲基化。在接受抗 PD-1 治疗的 129 名黑色素瘤患者的多中心队列中，使用定量甲基化特异性 PCR 验证了 PD-L2 甲基化的预后和预测价值。Liu等人提供的121名接受抗PD-1治疗的黑色素瘤患者的mRNA测序数据。分析 PD-L2 mRNA 表达。我们发现黑色素瘤组织和细胞系中 PD-L2 甲基化与 mRNA 表达水平之间存在显着相关性。干扰素-γ 诱导型 PD-L2 蛋白表达与黑色素瘤细胞中 PD-L2 启动子甲基化相关。发现 PD-L2 DNA 启动子低甲基化和高 mRNA 表达是延长总生存期的有力预测因素。在接受抗 PD-1 治疗的患者的治疗前黑色素瘤样本中，低 PD-L2 DNA 甲基化和高 PD-L2 mRNA 表达预测更长的无进展生存期。PD-L2 表达似乎是通过 DNA 启动子甲基化来调节的。PD-L2 DNA 甲基化和 mRNA 表达可以预测接受抗 PD-1 免疫治疗的黑色素瘤患者的无进展生存期。PD-L2 的评估应包括在进一步的抗 PD-1 抗体临床试验中。