Prognostic and predictive value of PD-L2 DNA methylation and mRNA expression in melanoma.
Adult
Aged
Aged, 80 and over
Cell Line
/ metabolism
Cohort Studies
CpG Islands
/ genetics
DNA Methylation
/ genetics
Female
Gene Expression
/ genetics
Humans
Immune Checkpoint Inhibitors
/ pharmacology
Immunotherapy
/ methods
Male
Melanoma
/ diagnosis
Middle Aged
Predictive Value of Tests
Prognosis
Programmed Cell Death 1 Ligand 2 Protein
/ genetics
Progression-Free Survival
RNA, Messenger
/ genetics
Skin Neoplasms
/ pathology
Anti-PD-1 immunotherapy
DNA methylation
Melanoma
PD-L1
PD-L2
Predictive biomarker
Prognostic biomarker
Journal
Clinical epigenetics
ISSN: 1868-7083
Titre abrégé: Clin Epigenetics
Pays: Germany
ID NLM: 101516977
Informations de publication
Date de publication:
26 06 2020
26 06 2020
Historique:
received:
13
03
2020
accepted:
10
06
2020
entrez:
27
6
2020
pubmed:
27
6
2020
medline:
19
8
2021
Statut:
epublish
Résumé
PD-L1 (programmed cell death 1 ligand 1) expression in melanoma has been associated with a better response to anti-PD-1 (programmed cell death 1) therapy. However, patients with PD-L1-negative melanomas can respond to anti-PD-1 blockade, suggesting that the other PD-1 ligand, PD-L2 (programmed cell death 1 ligand 2), might also be relevant for efficacy of PD-1 inhibition. We investigated PD-L2 expression and methylation as a prognostic and predictive biomarker in melanoma. DNA methylation at five CpG loci and gene expression of PD-L2 were evaluated with regard to survival in 470 melanomas from The Cancer Genome Atlas. PD-L2 promoter methylation in correlation with PD-L2 mRNA and protein expression was analyzed in human melanoma cell lines. Prognostic and predictive value of PD-L2 methylation was validated using quantitative methylation-specific PCR in a multicenter cohort of 129 melanoma patients receiving anti-PD-1 therapy. mRNA sequencing data of 121 melanoma patients receiving anti-PD-1 therapy provided by Liu et al. were analyzed for PD-L2 mRNA expression. We found significant correlations between PD-L2 methylation and mRNA expression levels in melanoma tissues and cell lines. Interferon-γ inducible PD-L2 protein expression correlated with PD-L2 promoter methylation in melanoma cells. PD-L2 DNA promoter hypomethylation and high mRNA expression were found to be strong predictors of prolonged overall survival. In pre-treatment melanoma samples from patients receiving anti-PD-1 therapy, low PD-L2 DNA methylation and high PD-L2 mRNA expression predicted longer progression-free survival. PD-L2 expression seems to be regulated via DNA promoter methylation. PD-L2 DNA methylation and mRNA expression may predict progression-free survival in melanoma patients receiving anti-PD-1 immunotherapy. Assessment of PD-L2 should be included in further clinical trials with anti-PD-1 antibodies.
Sections du résumé
BACKGROUND
PD-L1 (programmed cell death 1 ligand 1) expression in melanoma has been associated with a better response to anti-PD-1 (programmed cell death 1) therapy. However, patients with PD-L1-negative melanomas can respond to anti-PD-1 blockade, suggesting that the other PD-1 ligand, PD-L2 (programmed cell death 1 ligand 2), might also be relevant for efficacy of PD-1 inhibition. We investigated PD-L2 expression and methylation as a prognostic and predictive biomarker in melanoma.
METHODS
DNA methylation at five CpG loci and gene expression of PD-L2 were evaluated with regard to survival in 470 melanomas from The Cancer Genome Atlas. PD-L2 promoter methylation in correlation with PD-L2 mRNA and protein expression was analyzed in human melanoma cell lines. Prognostic and predictive value of PD-L2 methylation was validated using quantitative methylation-specific PCR in a multicenter cohort of 129 melanoma patients receiving anti-PD-1 therapy. mRNA sequencing data of 121 melanoma patients receiving anti-PD-1 therapy provided by Liu et al. were analyzed for PD-L2 mRNA expression.
RESULTS
We found significant correlations between PD-L2 methylation and mRNA expression levels in melanoma tissues and cell lines. Interferon-γ inducible PD-L2 protein expression correlated with PD-L2 promoter methylation in melanoma cells. PD-L2 DNA promoter hypomethylation and high mRNA expression were found to be strong predictors of prolonged overall survival. In pre-treatment melanoma samples from patients receiving anti-PD-1 therapy, low PD-L2 DNA methylation and high PD-L2 mRNA expression predicted longer progression-free survival.
CONCLUSION
PD-L2 expression seems to be regulated via DNA promoter methylation. PD-L2 DNA methylation and mRNA expression may predict progression-free survival in melanoma patients receiving anti-PD-1 immunotherapy. Assessment of PD-L2 should be included in further clinical trials with anti-PD-1 antibodies.
Identifiants
pubmed: 32586358
doi: 10.1186/s13148-020-00883-9
pii: 10.1186/s13148-020-00883-9
pmc: PMC7318478
doi:
Substances chimiques
Immune Checkpoint Inhibitors
0
Programmed Cell Death 1 Ligand 2 Protein
0
RNA, Messenger
0
Types de publication
Comparative Study
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
94Références
Methods Mol Biol. 2018;1708:621-641
pubmed: 29224167
Nat Biotechnol. 2012 May;30(5):413-21
pubmed: 22544022
Genes Immun. 2010 Jan;11(1):55-66
pubmed: 19710692
N Engl J Med. 2017 Nov 9;377(19):1824-1835
pubmed: 28891423
Leukemia. 2017 Mar;31(3):738-743
pubmed: 27840427
Cell. 2015 Jun 18;161(7):1681-96
pubmed: 26091043
FEBS Open Bio. 2019 Jun;9(6):1063-1070
pubmed: 31090214
Cancer Cell. 2019 Aug 12;36(2):168-178.e4
pubmed: 31327656
Clin Cancer Res. 2020 Apr 1;26(7):1725-1735
pubmed: 31732522
Hum Mol Genet. 2014 Jan 1;23(1):226-38
pubmed: 24014427
Medicine (Baltimore). 2017 May;96(18):e6369
pubmed: 28471952
J Clin Invest. 2017 Aug 1;127(8):2930-2940
pubmed: 28650338
Lancet Oncol. 2016 Dec;17(12):e542-e551
pubmed: 27924752
Nature. 2004 May 27;429(6990):457-63
pubmed: 15164071
Cell. 2017 Jun 29;170(1):142-157.e19
pubmed: 28648661
J Exp Med. 2001 Apr 2;193(7):839-46
pubmed: 11283156
Eur J Immunol. 2007 Sep;37(9):2405-10
pubmed: 17683117
Nat Med. 2019 Dec;25(12):1916-1927
pubmed: 31792460
J Am Acad Dermatol. 2017 Sep;77(3):534-542
pubmed: 28728868
Biochem Biophys Res Commun. 2003 Aug 1;307(3):672-7
pubmed: 12893276
Clin Cancer Res. 2014 Oct 1;20(19):5064-74
pubmed: 24714771
JCI Insight. 2018 Jul 12;3(13):
pubmed: 29997292
Pigment Cell Melanoma Res. 2019 May;32(3):435-440
pubmed: 30343532
N Engl J Med. 2012 Jun 28;366(26):2443-54
pubmed: 22658127
Oncotarget. 2016 Nov 29;7(48):79943-79955
pubmed: 27835597
Immunity. 2016 Nov 15;45(5):1148-1161
pubmed: 27851915
Ann Transl Med. 2017 Oct;5(19):389
pubmed: 29114547
Oncoimmunology. 2017 Feb 16;6(3):e1288329
pubmed: 28405520
Nature. 2014 Nov 27;515(7528):563-7
pubmed: 25428504
Oncoimmunology. 2016 Sep 2;5(10):e1221555
pubmed: 27853645
N Engl J Med. 2018 May 10;378(19):1789-1801
pubmed: 29658430
BMC Bioinformatics. 2011 Aug 04;12:323
pubmed: 21816040
Nat Commun. 2017 Feb 21;8:14572
pubmed: 28220772
Clin Cancer Res. 2017 Jun 15;23(12):3158-3167
pubmed: 28619999
Trends Genet. 2003 Nov;19(11):640-8
pubmed: 14585616
Immunity. 2018 Apr 17;48(4):812-830.e14
pubmed: 29628290
Oncotarget. 2017 Dec 7;9(1):641-650
pubmed: 29416641
Cancer. 2010 Apr 1;116(7):1757-66
pubmed: 20143437
J Clin Oncol. 2012 Jul 20;30(21):2678-83
pubmed: 22711850
Epigenomics. 2019 May;11(6):639-653
pubmed: 30821175
J Immunol. 2013 Sep 15;191(6):3419-29
pubmed: 23956425
Mol Immunol. 2011 Sep;48(15-16):2214-9
pubmed: 21752471
Nat Rev Genet. 2012 May 29;13(7):484-92
pubmed: 22641018
Cancer Immunol Res. 2017 Feb;5(2):106-117
pubmed: 28073774
Oncoimmunology. 2016 Sep 20;5(11):e1235107
pubmed: 27999753
EBioMedicine. 2018 Feb;28:97-104
pubmed: 29396294
Nat Rev Cancer. 2019 Mar;19(3):133-150
pubmed: 30755690