title: The polycomb group proteins, BMI-1 and EZH2, are tumour-associated antigens.
abstract: We used SEREX technology to identify novel tumour-associated antigens in patients with primary hepatocellular carcinoma and found serological responses to the polycomb group (PcG) protein BMI-1, which is overexpressed in a range of different tumour types. Further studies identified T-cell responses to both BMI-1 and another PcG protein, EZH2, in cancer patients and at relatively lower levels in some normal donors. We next identified several CD8+ T-cell epitopes derived from BMI-1 and EZH2 and demonstrated that EZH2-derived peptides elicited more significant interferon-gamma (IFN-gamma) release than BMI-1-derived peptides. That CD8(+) T cells were responsible for the observed responses was confirmed for EZH2 by both IFN-gamma capture assays and tetramer staining using an HLA-A0201-restricted, EZH2-derived YMSCSFLFNL (aa 666-674) epitope. The ability of YMSCSFLFNL (aa 666-674) to stimulate the in vitro expansion of specific T cells from peripheral blood lymphocytes was greatly enhanced when the CD25(+) T-cell population was depleted. EZH2-specific cytotoxic T lymphocyte clones specific for two HLA-A0201 epitopes were generated and found to recognise endogenously processed EZH2 in both HLA-matched fibroblasts and tumour cell lines. Given the widespread overexpression of PcG proteins in cancer and their critical role in oncogenesis, these data suggest that they may be useful targets for cancer immunotherapy.
authors.affiliation: Cancer Research UK Institute for Cancer Studies, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. j.c.steele@bham.ac.uk
authors.forename: J C
authors.initials: JC
authors.lastname: Steele
authors.forename: E E
authors.initials: EE
authors.lastname: Torr
authors.forename: K L
authors.initials: KL
authors.lastname: Noakes
authors.forename: E
authors.initials: E
authors.lastname: Kalk
authors.forename: P A
authors.initials: PA
authors.lastname: Moss
authors.forename: G M
authors.initials: GM
authors.lastname: Reynolds
authors.forename: S G
authors.initials: SG
authors.lastname: Hubscher
authors.forename: M
authors.initials: M
authors.lastname: van Lohuizen
authors.forename: D H
authors.initials: DH
authors.lastname: Adams
authors.forename: L S
authors.initials: LS
authors.lastname: Young
mesh_terms: D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm / Q000032:analysis / Q000235:genetics; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics*; D000071221:Enhancer of Zeste Homolog 2 Protein; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000096:biosynthesis; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics*; D063150:Polycomb Repressive Complex 1; D063151:Polycomb Repressive Complex 2; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000032:analysis / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics*
chemical_list: D000951:Antigens, Neoplasm; C069077:BMI1 protein, human; D004268:DNA-Binding Proteins; D053645:Interleukin-2 Receptor alpha Subunit; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D014157:Transcription Factors; D007371:Interferon-gamma; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D063150:Polycomb Repressive Complex 1