Analysis of DNA methylation patterns in the tumor immune microenvironment of metastatic melanoma.
B-Lymphocytes
/ cytology
Carcinoma
/ genetics
Cell Line, Tumor
Cohort Studies
CpG Islands
DNA Methylation
Databases, Genetic
Dendritic Cells
/ cytology
Epigenesis, Genetic
Gene Expression Regulation, Neoplastic
/ immunology
Glioma
/ genetics
Humans
Killer Cells, Natural
/ cytology
Lymphocytes
/ cytology
Macrophages
/ cytology
Melanoma
/ genetics
Mesothelioma
/ genetics
Microphthalmia-Associated Transcription Factor
/ metabolism
Myeloid Cells
/ cytology
Neoplasm Metastasis
/ genetics
PTEN Phosphohydrolase
/ genetics
Promoter Regions, Genetic
Skin Neoplasms
/ genetics
T-Lymphocytes
/ cytology
Tumor Microenvironment
/ immunology
DNA methylation
immune cells
melanoma
pan-cancer
tumor microenvironment
Journal
Molecular oncology
ISSN: 1878-0261
Titre abrégé: Mol Oncol
Pays: United States
ID NLM: 101308230
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
08
11
2019
revised:
03
02
2020
accepted:
05
03
2020
pubmed:
10
3
2020
medline:
11
5
2021
entrez:
10
3
2020
Statut:
ppublish
Résumé
The presence of immune cells in the tumor microenvironment has been associated with response to immunotherapies across several cancer types, including melanoma. Despite its therapeutic relevance, characterization of the melanoma immune microenvironments remains insufficiently explored. To distinguish the immune microenvironment in a cohort of 180 metastatic melanoma clinical specimens, we developed a method using promoter CpG methylation of immune cell type-specific genes extracted from genome-wide methylation arrays. Unsupervised clustering identified three immune methylation clusters with varying levels of immune CpG methylation that are related to patient survival. Matching protein and gene expression data further corroborated the identified epigenetic characterization. Exploration of the possible immune exclusion mechanisms at play revealed likely dependency on MITF protein level and PTEN loss-of-function events for melanomas unresponsive to immunotherapies (immune-low). To understand whether melanoma tumors resemble other solid tumors in terms of immune methylation characteristics, we explored 15 different solid tumor cohorts from TCGA. Low-dimensional projection based on immune cell type-specific methylation revealed grouping of the solid tumors in line with melanoma immune methylation clusters rather than tumor types. Association of survival outcome with immune cell type-specific methylation differed across tumor and cell types. However, in melanomas immune cell type-specific methylation was associated with inferior patient survival. Exploration of the immune methylation patterns in a pan-cancer context suggested that specific immune microenvironments might occur across the cancer spectrum. Together, our findings underscore the existence of diverse immune microenvironments, which may be informative for future immunotherapeutic applications.
Identifiants
pubmed: 32147909
doi: 10.1002/1878-0261.12663
pmc: PMC7191190
doi:
Substances chimiques
MITF protein, human
0
Microphthalmia-Associated Transcription Factor
0
PTEN Phosphohydrolase
EC 3.1.3.67
PTEN protein, human
EC 3.1.3.67
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
933-950Informations de copyright
© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.
Références
Nat Commun. 2018 Nov 6;9(1):4627
pubmed: 30401823
Trends Mol Med. 2006 Sep;12(9):406-14
pubmed: 16899407
Immunity. 2013 Oct 17;39(4):782-95
pubmed: 24138885
Proc Natl Acad Sci U S A. 2011 Oct 4;108(40):16723-8
pubmed: 21933959
Nat Rev Cancer. 2018 Mar;18(3):139-147
pubmed: 29326431
Nat Commun. 2018 Nov 8;9(1):4692
pubmed: 30410077
Cell. 2002 Jun 14;109(6):707-18
pubmed: 12086670
Science. 2017 Jul 28;357(6349):409-413
pubmed: 28596308
N Engl J Med. 2018 Aug 23;379(8):722-730
pubmed: 30134131
Annu Rev Genet. 2004;38:365-411
pubmed: 15568981
Cell Mol Life Sci. 2012 May;69(9):1475-91
pubmed: 22076652
J Cell Biol. 2002 Sep 16;158(6):1079-87
pubmed: 12235125
BMC Bioinformatics. 2012 May 08;13:86
pubmed: 22568884
Cancer Discov. 2017 Dec;7(12):1420-1435
pubmed: 29025772
Cell. 2017 Nov 2;171(4):934-949.e16
pubmed: 29033130
Biomed Res Int. 2017;2017:4719194
pubmed: 28770222
Science. 2015 Oct 9;350(6257):207-211
pubmed: 26359337
Cell. 2018 Nov 1;175(4):998-1013.e20
pubmed: 30388456
Anal Biochem. 2010 May 1;400(1):110-7
pubmed: 20079706
N Engl J Med. 2010 Aug 19;363(8):711-23
pubmed: 20525992
Cancer Res. 2003 Jun 1;63(11):2881-90
pubmed: 12782594
Oncotarget. 2017 Oct 31;8(62):106132-106142
pubmed: 29285320
Proc Natl Acad Sci U S A. 2016 Nov 29;113(48):E7759-E7768
pubmed: 27837020
Lancet Oncol. 2015 Apr;16(4):375-84
pubmed: 25795410
Nature. 2020 Jan;577(7791):549-555
pubmed: 31942075
Front Oncol. 2014 Dec 17;4:367
pubmed: 25566505
N Engl J Med. 2015 Jun 25;372(26):2509-20
pubmed: 26028255
Pigment Cell Res. 2006 Aug;19(4):290-302
pubmed: 16827748
Cell. 2018 Nov 1;175(4):984-997.e24
pubmed: 30388455
Cancer Cell. 2019 Feb 11;35(2):238-255.e6
pubmed: 30753825
PLoS One. 2012;7(7):e41361
pubmed: 22848472
Clin Dev Immunol. 2011;2011:947858
pubmed: 22046194
J Invest Dermatol. 2015 Jul;135(7):1820-1828
pubmed: 25705847
Nature. 2005 Feb 17;433(7027):764-9
pubmed: 15716956
N Engl J Med. 2017 Nov 9;377(19):1824-1835
pubmed: 28891423
Science. 2017 Jan 20;355(6322):
pubmed: 28104840
Proc Natl Acad Sci U S A. 2018 Feb 13;115(7):E1540-E1549
pubmed: 29386395
N Engl J Med. 2011 Jun 30;364(26):2507-16
pubmed: 21639808
Cancer Immunol Res. 2018 Sep;6(9):990-1000
pubmed: 30181337
Oncotarget. 2015 May 20;6(14):12297-309
pubmed: 25909218
Mol Cell Biol. 2006 Dec;26(23):8914-27
pubmed: 17000761
Lancet Oncol. 2012 May;13(5):459-65
pubmed: 22456429
Lancet Respir Med. 2018 Oct;6(10):771-781
pubmed: 30100403
J Clin Oncol. 2019 Jan 1;37(1):52-60
pubmed: 30407895
N Engl J Med. 2015 Jan 1;372(1):30-9
pubmed: 25399551
Nature. 2018 Mar 22;555(7697):469-474
pubmed: 29539639
Blood. 2018 May 3;131(18):2007-2015
pubmed: 29514782
Science. 2016 Apr 8;352(6282):227-31
pubmed: 26966191
Mol Cancer Ther. 2015 Apr;14(4):847-56
pubmed: 25695955
Mol Cancer Res. 2006 Oct;4(10):779-92
pubmed: 17050671
Cell. 2015 Jun 18;161(7):1681-96
pubmed: 26091043
Ann Am Thorac Soc. 2017 Aug;14(8):1248-1260
pubmed: 28613923
Nat Commun. 2014 Dec 15;5:5712
pubmed: 25502142
Cancer Treat Rev. 2014 Oct;40(9):1056-64
pubmed: 25060490
Genome Biol. 2015 Mar 31;16:64
pubmed: 25853550
Science. 2018 Oct 12;362(6411):
pubmed: 30309915
Immunity. 2018 Apr 17;48(4):812-830.e14
pubmed: 29628290
Mol Cell. 2012 Aug 24;47(4):633-47
pubmed: 22841485
Nat Commun. 2019 Sep 19;10(1):4278
pubmed: 31537801
Science. 2018 Jan 5;359(6371):104-108
pubmed: 29302014
Oncogene. 2019 May;38(19):3616-3635
pubmed: 30651597
Science. 2018 Jan 5;359(6371):97-103
pubmed: 29097493
J Pathol. 2014 May;233(1):39-50
pubmed: 24399611
J Invest Dermatol. 2016 May;136(5):1002-1011
pubmed: 26854490
Nature. 2020 Jan;577(7791):561-565
pubmed: 31942071
Ann Oncol. 2019 Jan 1;30(1):44-56
pubmed: 30395155
N Engl J Med. 2017 Oct 5;377(14):1345-1356
pubmed: 28889792
Cancer Discov. 2016 Feb;6(2):202-16
pubmed: 26645196
Nature. 2005 Jul 7;436(7047):117-22
pubmed: 16001072
Nat Commun. 2018 Nov 29;9(1):5068
pubmed: 30498206
Science. 2016 Apr 8;352(6282):189-96
pubmed: 27124452
Curr Oncol Rep. 2008 Sep;10(5):439-46
pubmed: 18706274
Mol Cancer Ther. 2017 Nov;16(11):2598-2608
pubmed: 28835386
Oncotarget. 2018 Apr 17;9(29):20826-20837
pubmed: 29755693
Nature. 2015 Jul 9;523(7559):231-5
pubmed: 25970248