Publication

Prognostic and predictive value of PD-L2 DNA methylation and mRNA expression in melanoma

Journal Paper/Review - Jun 26, 2020

Units
PubMed
Doi

Citation
Hoffmann F, Landsberg J, Kristiansen G, Flatz L, Pietsch T, Dietrich J, Ring S, Gielen G, Strieth S, Kuster P, Saavedra G, Brossart P, Holderried T, Posch C, Fröhlich A, Sirokay J, Niebel D, Zarbl R, Dietrich D. Prognostic and predictive value of PD-L2 DNA methylation and mRNA expression in melanoma. Clin Epigenetics 2020; 12:94.
Type
Journal Paper/Review (English)
Journal
Clin Epigenetics 2020; 12
Publication Date
Jun 26, 2020
Issn Electronic
1868-7083
Pages
94
Brief description/objective

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.