PD-L1 (CD274) and PD-L2 (PDCD1LG2) promoter methylation is associated with HPV infection and transcriptional repression in head and neck squamous cell carcinomas
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Alina Franzen1, Timo J. Vogt1, Tim Müller2, Jörn Dietrich1, Andreas Schröck1, Carsten Golletz2, Peter Brossart3, Friedrich Bootz1, Jennifer Landsberg4, Glen Kristiansen2 and Dimo Dietrich1
1Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Bonn, Germany
2Institute of Pathology, University Hospital Bonn, Bonn, Germany
3Department of Oncology, Hematology and Rheumatology, University Hospital Bonn, Bonn, Germany
4Department of Dermatology, Bonn, University Hospital Bonn, Germany
Dimo Dietrich, email: [email protected]
Keywords: PD-L1; PD-1; PD-L2; CD274; PDCD1LG2
Received: May 31, 2017 Accepted: November 15, 2017 Published: December 07, 2017
Background: DNA methylation of the immune checkpoint gene PD-L1 has recently been shown to be associated with PD-L1 mRNA expression in various malignancies. This study aimed to investigate the association of PD-L1 and PD-L2 methylation with mRNA expression, immune cell infitration, protein expression and human papilloma virus (HPV) infection in head and neck squamous cell carcinoma (HNSCC) patients.
Results: DNA methylation of PD-L1 and PD-L2 correlates inversely with mRNA expression (PD-L1: p ≤ 0.002; PD-L2: p ≤ 0.014). Methylation of specific CpG-sites of both PD-L1 and PD-L2 were further significantly associated with HPV infection in the TCGA cohort. Immune cell infiltrates correlated significantly with PD-L1 and PD-L2 methylation. In the validation cohort, PD-L1 protein expression was associated with PD-L1 hypomethylation (p = 0.012).
Conclusions: DNA methylation of PD-L1 and PD-L2 is associated with transcriptional silencing and HPV infection in HNSCCs. Additional studies are warranted to test PD-L1 and PD-L2 methylation as predictive biomarkers for response to immunotherapies (e.g. pembrolizumab and nivolumab) that target the PD-L1/ PD-L2/PD-1 immune checkpoint axis.
Materials and Methods: PD-L1 and PD-L2 promoter methylation and its mRNA expression were analyzed based on Infinium HumanMethylation450 BeadChip and RNA-Seq (both Illumina, Inc.) data in a representative HNSCC patient cohort (n = 528) enrolled by The Cancer Genome Atlas (TCGA) Research Network. A validation cohort consisting of 168 HNSCC patients treated at the University Hospital Bonn was analyzed regarding PD-L1 and PD-L2 promoter methylation by means of methylation-specific quantitative real-time PCR. PD-L1 protein expression in the validation cohort was quantified via immunohistochemistry (PD-L1 antibody clone 22C3, Dako/Agilent Technologies, Inc.).
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