title: Identification of a new HLA-A*0201-restricted cryptic epitope from CYP1B1.
abstract: Cytochrome P450 1B1 (CYP1B1) was recently shown to be a candidate tumor antigen broadly expressed in solid and hematologic malignancies. Nevertheless, use of such self-antigens as targets for immune intervention can be limited because of loss of high-avidity T cells during negative selection in the thymus. Recent data suggest that targeting of cryptic epitopes may represent a way to circumvent such self-tolerance and induce efficient antitumor CTL responses. Here, we present the identification and characterization of a novel, cryptic HLA-A*0201-binding peptide from CYP1B1. The nanomer CYP246 was identified by epitope deduction using algorithms to predict HLA-A*0201-binding peptides. CYP246 is characterized by strong initial HLA-A*0201 binding but a short MHC/peptide binding half-life. Expansion of high-avidity CTL was readily possible using autologous CD40-activated B cells from normal donors and cancer patients as antigen-presenting cells, suggesting that an intact T-cell repertoire can be expanded for this epitope. Lysis of CYP1B1-expressing, HLA-A*0201+ tumor cell lines and primary tumor cells confirmed that sufficient levels of CYP246 are presented by tumor cells for effector CTL killing. These findings indicate that CYP246 is a candidate cryptic epitope for immune interventions in which tumor CYP1B1 is targeted.
authors.affiliation: Department of Adult Oncology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA, USA.
authors.forename: Britta
authors.initials: B
authors.lastname: Maecker
authors.forename: Michael S
authors.initials: MS
authors.lastname: von Bergwelt-Baildon
authors.forename: David H
authors.initials: DH
authors.lastname: Sherr
authors.forename: Lee M
authors.initials: LM
authors.lastname: Nadler
authors.forename: Joachim L
authors.initials: JL
authors.lastname: Schultze
mesh_terms: D000465:Algorithms; D000938:Antigen-Presenting Cells / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases / Q000276:immunology* / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology / Q000378:metabolism; D000939:Epitopes; D015234:HLA-A Antigens / Q000276:immunology* / Q000378:metabolism; D015789:HLA-A2 Antigen; D006207:Half-Life; D006801:Humans; D008223:Lymphoma / Q000276:immunology* / Q000378:metabolism; D009101:Multiple Myeloma / Q000276:immunology* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000276:immunology / Q000378:metabolism; D010446:Peptide Fragments / Q000276:immunology* / Q000378:metabolism; D000072516:Retinoic Acid 4-Hydroxylase; D013601:T-Lymphocytes / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D019013:CD40 Antigens; D000939:Epitopes; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; C072013:MAGEA3 protein, human; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1; D000072516:Retinoic Acid 4-Hydroxylase