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- Title
Prognostic and predictive value of PD-L2 DNA methylation and mRNA expression in melanoma.
- Authors
Hoffmann, Friederike; Zarbl, Romina; Niebel, Dennis; Sirokay, Judith; Fröhlich, Anne; Posch, Christian; Holderried, Tobias A. W.; Brossart, Peter; Saavedra, Gonzalo; Kuster, Pia; Strieth, Sebastian; Gielen, Gerrit H.; Ring, Sandra S.; Dietrich, Jörn; Pietsch, Torsten; Flatz, Lukas; Kristiansen, Glen; Landsberg, Jennifer; Dietrich, Dimo
- Abstract
Background: 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. Methods: 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. Results: 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. Conclusion: 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.
- Subjects
PROGRAMMED cell death 1 receptors; PROGRAMMED death-ligand 1; DNA methylation
- Publication
Clinical Epigenetics, 2020, Vol 12, Issue 1, p1
- ISSN
1868-7075
- Publication type
Article
- DOI
10.1186/s13148-020-00883-9