DNA methylation of indoleamine 2,3-dioxygenase 1 (IDO1) in head and neck squamous cell carcinomas correlates with IDO1 expression, HPV status, patients’ survival, immune cell infiltrates, mutational load, and interferon γ signature
Verena Sailer,
Ulrike Sailer,
Emma Grace Bawden,
Romina Zarbl,
Constanze Wiek,
Timo J. Vogt,
Joern Dietrich,
Sophia Loick,
Ingela Grünwald,
Marieta Toma,
Carsten Golletz,
Andreas Gerstner,
Glen Kristiansen,
Friedrich Bootz,
Kathrin Scheckenbach,
Jennifer Landsberg,
Dimo Dietrich
Affiliations
Verena Sailer
Pathology of the University Hospital Schleswig-Holstein, Campus Luebeck, Luebeck, Germany
Ulrike Sailer
Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Sigmund-Freud-Street 25, 53105 Bonn, Germany
Emma Grace Bawden
Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
Romina Zarbl
Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Sigmund-Freud-Street 25, 53105 Bonn, Germany
Constanze Wiek
Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Düsseldorf, Düsseldorf, Germany
Timo J. Vogt
Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Sigmund-Freud-Street 25, 53105 Bonn, Germany
Joern Dietrich
Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Sigmund-Freud-Street 25, 53105 Bonn, Germany
Sophia Loick
Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Sigmund-Freud-Street 25, 53105 Bonn, Germany
Ingela Grünwald
Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Sigmund-Freud-Street 25, 53105 Bonn, Germany
Marieta Toma
Institute of Pathology, University Hospital Bonn, Bonn, Germany
Carsten Golletz
Institute of Pathology, University Hospital Bonn, Bonn, Germany
Andreas Gerstner
Department of Otolaryngology, Head and Neck Surgery, Municipal Hospital Braunschweig, Braunschweig, Germany
Glen Kristiansen
Institute of Pathology, University Hospital Bonn, Bonn, Germany
Friedrich Bootz
Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Sigmund-Freud-Street 25, 53105 Bonn, Germany
Kathrin Scheckenbach
Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Düsseldorf, Düsseldorf, Germany
Jennifer Landsberg
Department of Dermatology and Allergy, University Hospital Bonn, Bonn, Germany
Dimo Dietrich
Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Sigmund-Freud-Street 25, 53105 Bonn, Germany; Corresponding author.
Background: The immune checkpoint, indoleamine 2,3-dioxygenase 1, is under investigation as target of novel immunotherapies for cancers, including head and neck squamous cell carcinomas (HNSCC). The aim of our study was to analyze DNA methylation of the encoding gene (IDO1) in HNSCC. Methods: Methylation of three CpG sites within the promoter, promoter flank, and gene body was investigated and correlated with mRNA expression, immune cell infiltration, mutational burden, human papillomavirus (HPV)-status, and overall survival in a cohort of N = 528 HNSCC patients obtained from The Cancer Genome Atlas. In addition, IDO1 immunohistochemistry and DNA methylation analysis was performed in an independent cohort of N = 138 HNSCC samples. Findings: Significant inverse correlations of IDO1 methylation and IDO1 mRNA expression were found in the promoter and promoter flank region (Spearman's ρ = −0.163 and ρ = −0.377, respectively) while a positive correlation was present in the gene body (ρ = 0.502; all P < 0.001). IDO1 DNA methylation significantly correlated with IDO1 protein expressing immune cells as well as tumor cells. IDO1 promoter flank hypermethylation was significantly associated with poor overall survival (P < 0.001). In addition, we discovered significant correlations between IDO1 methylation and expression with RNA signatures of immune cell infiltrates and with HPV-status, mutational load (methylation only), and interferon γ signature. Interpretation: Our results suggest IDO1 expression levels are epigenetically regulated by DNA methylation. This study provides rationale to test IDO1 methylation as potential biomarker for prediction of response to IDO1 immune checkpoint inhibitors in HNSCC. Keywords: Indoleamine 2,3-dioxygenase 1, IDO1, Biomarker, DNA methylation, Head and neck squamous cell carcinoma, HPV, Immunotherapy, Prognosis, Prediction
