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.
Biomarkers, Tumor
Cell Line, Tumor
Cluster Analysis
CpG Islands
Cytokines
/ metabolism
DNA Methylation
Female
Gene Expression Regulation, Neoplastic
Humans
Immunohistochemistry
Indoleamine-Pyrrole 2,3,-Dioxygenase
/ genetics
Kaplan-Meier Estimate
Male
Papillomaviridae
Papillomavirus Infections
/ complications
RNA, Messenger
/ genetics
Squamous Cell Carcinoma of Head and Neck
/ etiology
DNA methylation
HPV
Head and neck squamous cell carcinoma
IDO1, Biomarker
Immunotherapy
Indoleamine 2,3-dioxygenase 1
Prediction
Prognosis
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Oct 2019
Oct 2019
Historique:
received:
11
03
2019
revised:
19
09
2019
accepted:
24
09
2019
pubmed:
20
10
2019
medline:
20
3
2020
entrez:
20
10
2019
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
BACKGROUND
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
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
RESULTS
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
CONCLUSIONS
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.
Identifiants
pubmed: 31628024
pii: S2352-3964(19)30649-8
doi: 10.1016/j.ebiom.2019.09.038
pmc: PMC6838413
pii:
doi:
Substances chimiques
Biomarkers, Tumor
0
Cytokines
0
IDO1 protein, human
0
Indoleamine-Pyrrole 2,3,-Dioxygenase
0
RNA, Messenger
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
341-352Informations de copyright
Crown Copyright © 2019. Published by Elsevier B.V. All rights reserved.
Références
Epigenomics. 2013;5(5):553-68
pubmed: 24059801
Cancer Res. 2012 Nov 15;72(22):5649-57
pubmed: 23144293
Rejuvenation Res. 2012 Oct;15(5):483-94
pubmed: 23098078
N Engl J Med. 2016 Nov 10;375(19):1856-1867
pubmed: 27718784
Nat Rev Genet. 2005 Aug;6(8):597-610
pubmed: 16136652
Nat Rev Cancer. 2016 May;16(5):275-87
pubmed: 27079802
Nature. 2015 Jan 29;517(7536):576-82
pubmed: 25631445
J Clin Invest. 2017 Aug 1;127(8):2930-2940
pubmed: 28650338
Science. 2015 Apr 3;348(6230):124-8
pubmed: 25765070
Cell. 2017 Jun 29;170(1):142-157.e19
pubmed: 28648661
Oncogene. 2019 May;38(19):3551-3568
pubmed: 30655605
Lancet Oncol. 2016 Dec;17(12):e542-e551
pubmed: 27924752
Proc Natl Acad Sci U S A. 1986 Sep;83(17):6622-6
pubmed: 2428037
Ann Oncol. 2018 Nov 1;29(11):2247-2253
pubmed: 30219915
Oncoimmunology. 2017 Feb 10;6(3):e1273310
pubmed: 28405495
Eur J Cancer. 2019 Mar;109:154-161
pubmed: 30731276
Methods Mol Biol. 2004;287:207-18
pubmed: 15273414
Neoplasia. 2018 Feb;20(2):218-225
pubmed: 29331888
BioDrugs. 2018 Aug;32(4):311-317
pubmed: 29980987
JCI Insight. 2018 Jul 12;3(13):
pubmed: 29997292
Oncotarget. 2017 Jun 20;8(25):41011-41020
pubmed: 28487502
Pigment Cell Melanoma Res. 2019 May;32(3):435-440
pubmed: 30343532
CA Cancer J Clin. 2019 Jan;69(1):7-34
pubmed: 30620402
Oncotarget. 2016 Nov 29;7(48):79943-79955
pubmed: 27835597
Immunity. 2016 Nov 15;45(5):1148-1161
pubmed: 27851915
J Immunother Cancer. 2019 Jul 15;7(1):184
pubmed: 31307547
J Immunother Cancer. 2018 Jun 20;6(1):61
pubmed: 29921320
J Histochem Cytochem. 2009 May;57(5):477-89
pubmed: 19153192
Oncoimmunology. 2017 Feb 16;6(3):e1288329
pubmed: 28405520
Oncoimmunology. 2016 Sep 2;5(10):e1221555
pubmed: 27853645
EBioMedicine. 2017 Mar;17:223-236
pubmed: 28314692
Leukemia. 2017 Mar;31(3):738-743
pubmed: 27840427
Semin Immunopathol. 2019 Jan;41(1):41-48
pubmed: 30203227
Lancet Oncol. 2019 Aug;20(8):1083-1097
pubmed: 31221619
N Engl J Med. 2010 Jul 1;363(1):24-35
pubmed: 20530316
Clin Cancer Res. 2011 Nov 15;17(22):6985-91
pubmed: 22068654
Clin Cancer Res. 2019 Jun 1;25(11):3220-3228
pubmed: 30770348
J Clin Oncol. 2014 Oct 20;32(30):3365-73
pubmed: 24958820
Oral Oncol. 2018 Jun;81:45-51
pubmed: 29884413
Ann Oncol. 2017 Aug 1;28(8):1934-1941
pubmed: 28460011
Immunity. 2018 Apr 17;48(4):812-830.e14
pubmed: 29628290
Front Oncol. 2018 Oct 04;8:423
pubmed: 30338242
J Clin Oncol. 2018 Sep 28;:JCO2018789602
pubmed: 30265610
PLoS Genet. 2013;9(8):e1003678
pubmed: 23950730
Adv Exp Med Biol. 2016;879:71-90
pubmed: 26659264
Oncoimmunology. 2016 Nov 10;6(1):e1257454
pubmed: 28197377
Mod Pathol. 2016 Oct;29(10):1165-72
pubmed: 27389313
Oncotarget. 2017 Dec 7;9(1):641-650
pubmed: 29416641
Nat Commun. 2016 Nov 25;7:13507
pubmed: 27886173
J Mol Diagn. 2017 Jan;19(1):107-114
pubmed: 27939865
Nat Med. 2019 Mar;25(3):389-402
pubmed: 30842677
Nature. 2013 Oct 17;502(7471):333-339
pubmed: 24132290
Front Oncol. 2019 May 20;9:383
pubmed: 31165040
Cell Rep. 2017 May 9;19(6):1189-1201
pubmed: 28494868
Cancer Sci. 2019 Jun;110(6):1863-1871
pubmed: 31012515
Genome Med. 2013 Feb 05;5(2):15
pubmed: 23419152
J Immunol. 2013 Sep 15;191(6):3419-29
pubmed: 23956425
Cancer Res. 2017 Dec 15;77(24):6795-6811
pubmed: 29247038
CA Cancer J Clin. 2018 Nov;68(6):394-424
pubmed: 30207593
Sci Transl Med. 2013 Aug 28;5(200):200ra116
pubmed: 23986400
Cancer Cell. 2014 Oct 13;26(4):577-90
pubmed: 25263941
Methods Mol Biol. 2017;1589:139-159
pubmed: 26138988
EBioMedicine. 2018 Feb;28:97-104
pubmed: 29396294
Epigenetics. 2015;10(10):943-57
pubmed: 26291385
Int Rev Cell Mol Biol. 2018;336:175-203
pubmed: 29413890
Cell. 2016 Jul 28;166(3):740-754
pubmed: 27397505
Oncoimmunology. 2017 Jan 3;6(2):e1274477
pubmed: 28344890