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

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.

NLRC5/CITA expression correlates with efficient response to checkpoint blockade immunotherapy

“…S3). It appears that PD-L2 is the best variable to combine with NLRC5 and mutation number for purposes of prediction (Table S1) and is in line with PD-L2 being a predictive marker in anti-PD-1 checkpoint therapy 47 . Future discovery of other variables will further www.nature.com/scientificreports/ increase predictive power for response to the checkpoint therapy in melanoma.…”

CTLA4 promoter methylation predicts response and progression-free survival in stage IV melanoma treated with anti-CTLA-4 immunotherapy (ipilimumab)

“…Epigenetic alterations, however, have widely been neglected as potential predictive biomarkers so far but have great potential due to their significance in tumorigenesis and immunology, including immune cell differentiation and T cell exhaustion [8][9][10][11][12]. Recent reports suggest DNA methylation of genes encoding for the immune checkpoints 4-1BB, LAG-3, PD-L2, and CTLA-4 as predictive biomarkers for response to ICB in melanoma [13][14][15][16]. Our present study aimed at the analysis of the value of CTLA4 methylation as a biomarker to predict response and progression under CTLA-4-directed ICB monotherapy.…”

Interrogating Epigenome toward Personalized Approach in Cutaneous Melanoma

“…These two types of epigenetic changes appear to influence each other in the deposition during mammalian development and carcinogenesis; histone methylation appears to direct DNA methylation patterns, while DNA methylation may serve as a model for establishing certain histone changes [ 32 ]. Moreover, in CM, DNA methylation is gaining increased importance in PD-related immune therapy [ 48 ], while histone alterations are associated with BRAF-targeted therapy [ 49 ].…”