Background: The
adenosine A2a receptor (A2aR) and the
adenosine synthesizing
enzyme CD73 have recently evolved as a novel immunotherapeutic target. However, little is known about epigenetic modification of the encoding genes ADORA2A and NT5E. Methods: In the present study, we evaluated methylation at 23 loci of ADORA2A and 17 loci of NT5E with regard to transcriptional activity, human
papilloma virus (HPV) status, immune cell infiltration, and outcome in a cohort of 279 head and neck
squamous carcinoma (
HNSCC) patients obtained from The
Cancer Genome Atlas (TCGA). Methylation and
mRNA expression were generated by the Infinium HumanMethylation450 BeadChip and Illumina HiSeq 2000
RNA Sequencing Version 2 analysis (Illumina, Inc., San Diego, CA, USA). HPV status was assessed by
RNA-Seq data analysis of the viral genes E6 and E7. Results: Thirteen out of 23 ADORA2A loci and 15/17 NT5E loci were significantly correlated with
mRNA levels (p < 0.05). Inverse correlations were predominately found in promoter regions, while positive correlations were more profound at intragenic loci. ADORA2A hypermethylation was significantly associated with poor overall survival (OS, p ≤ 0.030), whereas NT5E hypomethylation was associated with decreased OS in HPV-positive
tumors (p ≤ 0.024) and increased OS in HPV-negative
HNSCC (p ≤ 0.029). Further, we found significant correlations between methylation and immune cell infiltrates. Conclusion: Our data might point towards a significant role of the A2aR/CD73 axis during
cancer progression in
HNSCC.