title: Melanoma-specific MHC-II expression represents a tumour-autonomous phenotype and predicts response to anti-PD-1/PD-L1 therapy.
abstract: Anti-PD-1 therapy yields objective clinical responses in 30-40% of advanced melanoma patients. Since most patients do not respond, predictive biomarkers to guide treatment selection are needed. We hypothesize that MHC-I/II expression is required for tumour antigen presentation and may predict anti-PD-1 therapy response. In this study, across 60 melanoma cell lines, we find bimodal expression patterns of MHC-II, while MHC-I expression was ubiquitous. A unique subset of melanomas are capable of expressing MHC-II under basal or IFNγ-stimulated conditions. Using pathway analysis, we show that MHC-II(+) cell lines demonstrate signatures of 'PD-1 signalling', 'allograft rejection' and 'T-cell receptor signalling', among others. In two independent cohorts of anti-PD-1-treated melanoma patients, MHC-II positivity on tumour cells is associated with therapeutic response, progression-free and overall survival, as well as CD4(+) and CD8(+) tumour infiltrate. MHC-II(+) tumours can be identified by melanoma-specific immunohistochemistry using commercially available antibodies for HLA-DR to improve anti-PD-1 patient selection.
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, 37232 Tennessee, USA.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Johnson
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, 37232 Tennessee, USA.
authors.forename: Monica V
authors.initials: MV
authors.lastname: Estrada
authors.affiliation: Department of Pathology, Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Boulevard de Waterloo 121, Brussels 1000, Belgium.
authors.forename: Roberto
authors.initials: R
authors.lastname: Salgado
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, 37232 Tennessee, USA.
authors.forename: Violeta
authors.initials: V
authors.lastname: Sanchez
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, 37232 Tennessee, USA.
authors.forename: Deon B
authors.initials: DB
authors.lastname: Doxie
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, 37232 Tennessee, USA.
authors.forename: Susan R
authors.initials: SR
authors.lastname: Opalenik
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, 37232 Tennessee, USA.|Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, 37232 Tennessee, USA.
authors.forename: Anna E
authors.initials: AE
authors.lastname: Vilgelm
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, 37232 Tennessee, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Feld
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, 37232 Tennessee, USA.
authors.forename: Adam S
authors.initials: AS
authors.lastname: Johnson
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, 37232 Tennessee, USA.|Department of Cancer Biology, Vanderbilt University, Nashville, 37232 Tennessee, USA.
authors.forename: Allison R
authors.initials: AR
authors.lastname: Greenplate
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, 37232 Tennessee, USA.
authors.forename: Melinda E
authors.initials: ME
authors.lastname: Sanders
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, 37232 Tennessee, USA.|Department of Cancer Biology, Vanderbilt University, Nashville, 37232 Tennessee, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Lovly
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, 02114 Massachusetts, USA.
authors.forename: Dennie T
authors.initials: DT
authors.lastname: Frederick
authors.affiliation: Department of Surgical Oncology, Vanderbilt University, Nashville, 37232 Tennessee, USA.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Kelley
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, 37232 Tennessee, USA.|Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, 37232 Tennessee, USA.
authors.forename: Ann
authors.initials: A
authors.lastname: Richmond
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, 37232 Tennessee, USA.|Department of Cancer Biology, Vanderbilt University, Nashville, 37232 Tennessee, USA.
authors.forename: Jonathan M
authors.identifier: http://orcid.org/0000-0001-9428-8866
authors.initials: JM
authors.lastname: Irish
authors.affiliation: Department of Biostatistics, Vanderbilt University, Nashville, 37232 Tennessee, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Shyr
authors.affiliation: Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, 37232 Tennessee, USA.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Sullivan
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, 37232 Tennessee, USA.
authors.forename: Igor
authors.initials: I
authors.lastname: Puzanov
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, 37232 Tennessee, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Sosman
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, 37232 Tennessee, USA.|Department of Cancer Biology, Vanderbilt University, Nashville, 37232 Tennessee, USA.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Balko
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D005802:Genes, MHC Class II / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000378:metabolism*; D000077594:Nivolumab; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D061026:Programmed Cell Death 1 Receptor; D012333:RNA, Messenger; D000077594:Nivolumab; C000594389:atezolizumab; C582435:pembrolizumab
references.citation: Pathol Res Pract. 2000;196(12):807-15
references.pmid: 11156321
references.citation: Nature. 2015 Jul 9;523(7559):231-5
references.pmid: 25970248
references.citation: Eur J Immunol. 2003 May;33(5):1183-92
references.pmid: 12731043
references.citation: J Exp Med. 1973 Nov 1;138(5):1044-55
references.pmid: 4583069
references.citation: J Natl Cancer Inst. 1981 Jun;66(6):1003-12
references.pmid: 7017212
references.citation: Nature. 1984 Dec 13-19;312(5995):639-41
references.pmid: 6334239
references.citation: Histopathology. 1992 May;20(5):411-6
references.pmid: 1587490
references.citation: Curr Biol. 2005 Sep 20;15(18):1629-39
references.pmid: 16169484
references.citation: Int Immunol. 2006 Nov;18(11):1591-602
references.pmid: 16987935
references.citation: Immunogenetics. 2007 Feb;59(2):123-33
references.pmid: 17180681
references.citation: Genes Chromosomes Cancer. 2010 Feb;49(2):144-54
references.pmid: 19862823
references.citation: Int J Cancer. 2010 Jul 15;127(2):249-56
references.pmid: 20178101
references.citation: J Clin Oncol. 2010 Jul 1;28(19):3167-75
references.pmid: 20516446
references.citation: Int J Oncol. 2011 Jun;38(6):1589-95
references.pmid: 21455572
references.citation: Exp Mol Med. 2011 May 31;43(5):281-90
references.pmid: 21464590
references.citation: J Immunother. 2012 Jan;35(1):66-72
references.pmid: 22130161
references.citation: Nature. 2011 Dec 22;480(7378):480-9
references.pmid: 22193102
references.citation: Nature. 2012 Mar 29;483(7391):603-7
references.pmid: 22460905
references.citation: N Engl J Med. 2012 Jun 28;366(26):2443-54
references.pmid: 22658127
references.citation: Nat Med. 2012 Jul;18(7):1052-9
references.pmid: 22683778
references.citation: Mol Cell Proteomics. 2012 Nov;11(11):1457-67
references.pmid: 22942358
references.citation: N Engl J Med. 2013 Jul 11;369(2):134-44
references.pmid: 23724846
references.citation: N Engl J Med. 2013 Jul 11;369(2):122-33
references.pmid: 23724867
references.citation: Cancer Res. 2013 Oct 15;73(20):6346-58
references.pmid: 23966295
references.citation: Lancet. 2014 Sep 20;384(9948):1109-17
references.pmid: 25034862
references.citation: Nature. 2014 Nov 27;515(7528):558-62
references.pmid: 25428503
references.citation: Nature. 2014 Nov 27;515(7528):563-7
references.pmid: 25428504
references.citation: Nature. 2014 Nov 27;515(7528):568-71
references.pmid: 25428505
references.citation: Nature. 2014 Nov 27;515(7528):572-6
references.pmid: 25428506
references.citation: N Engl J Med. 2014 Dec 4;371(23):2189-99
references.pmid: 25409260
references.citation: N Engl J Med. 2015 Jan 22;372(4):320-30
references.pmid: 25399552
references.citation: N Engl J Med. 2015 Jan 22;372(4):311-9
references.pmid: 25482239
references.citation: Cancer Immunol Res. 2015 Mar;3(3):288-95
references.pmid: 25736262
references.citation: Lancet Oncol. 2015 Mar;16(3):257-65
references.pmid: 25704439
references.citation: Science. 2015 Apr 3;348(6230):124-8
references.pmid: 25765070
references.citation: J Clin Oncol. 2015 May 1;33(13):1430-7
references.pmid: 25452452
references.citation: N Engl J Med. 2015 May 21;372(21):2018-28
references.pmid: 25891174
references.citation: N Engl J Med. 2015 May 21;372(21):2006-17
references.pmid: 25891304
references.citation: J Clin Oncol. 2015 Jun 20;33(18):2004-12
references.pmid: 25897158
references.citation: N Engl J Med. 2015 Jun 25;372(26):2521-32
references.pmid: 25891173
references.citation: Nat Commun. 2015;6:7458
references.pmid: 26109379
references.citation: N Engl J Med. 2015 Jul 2;373(1):23-34
references.pmid: 26027431
references.citation: Br J Cancer. 2003 Feb 10;88(3):424-31
references.pmid: 12569387