Abstract
BackgroundPD-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.MethodsDNA 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.ResultsWe 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.ConclusionPD-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.
Highlights
Progressive disease (PD)-L1 expression in melanoma has been associated with a better response to anti-Programmed cell death 1 (PD-1) therapy
We found significant inverse correlations between Programmed cell death ligand 2 (PD-L2) DNA methylation and Messenger ribonucleic acid (mRNA) expression levels at two out of five analyzed CpG sites (Table 1)
Methylation of the other CpGs within the promoter flanks and the gene body showed a significant positive correlation with mRNA expression. These results suggest that PD-L2 and Programmed cell death 1 ligand 1 (PD-L1) expression is regulated by gene methylation
Summary
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. 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 be relevant for efficacy of PD-1 inhibition. We investigated PD-L2 expression and methylation as a prognostic and predictive biomarker in melanoma. To allow for the development of accurate predictive and prognostic biomarkers, knowledge on the regulation of immune checkpoint genes is mandatory. PD-L2 expression can be induced by inflammatory cytokines on different immune and non-immune cells [5, 6] It can be expressed by tumor cells including melanoma [7, 8]. The epigenetic regulation with particular focus on DNA promoter methylation of the PD-L2 encoding gene, PDCD1LG2, has not been considered as a biomarker in the context of anti-PD-1 immunotherapies in melanoma
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