title: Identification of NY-ESO-1 peptide analogues capable of improved stimulation of tumor-reactive CTL.
abstract: Expression of NY-ESO-1 in a high proportion of different human tumors makes this protein a very attractive vaccine target. NY-ESO-1 peptides, recognized by HLA-A2-restricted CTL, have recently been described. However, it remains unclear how efficiently tumors generate these epitopes, and whether peptide analogues can be used for optimal expansion and activation of NY-ESO-1-specific HLA-A2-restricted CTL. By generating unique CTL clones, we demonstrate that NY-ESO-1-positive tumor cells are efficiently killed by HLA-A2-restricted CTL specific for the peptide epitope NY-ESO-1 157-165. Presentation of this epitope is not affected by the presence or absence of the proteasome subunits low molecular proteins 2 and 7 and is not blocked by proteasome inhibitors, while it is impaired in the TAP-deficient cell line LBL 721.174. NY-ESO-1 157-165 peptide analogues were compared for their antigenicity and immunogenicity using PBL from melanoma patients. Three peptides, containing the carboxyl-terminal cysteine substituted for either valine, isoleucine, or leucine, were recognized at least 100 times more efficiently than the wild-type peptide by specific CTL. Peptide analogues were capable of stimulating the expansion of NY-ESO-1-specific CTL from PBL of melanoma patients much more efficiently than wild-type peptide. These findings define the processing requirements for the generation of the NY-ESO-1 157-165 epitope. Identification of highly antigenic NY-ESO-1 peptide analogues may be important for the development of vaccines capable of expanding NY-ESO-1-specific CTL in cancer patients.
authors.affiliation: Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: J L
authors.initials: JL
authors.lastname: Chen
authors.forename: P R
authors.initials: PR
authors.lastname: Dunbar
authors.forename: U
authors.initials: U
authors.lastname: Gileadi
authors.forename: E
authors.initials: E
authors.lastname: Jäger
authors.forename: S
authors.initials: S
authors.lastname: Gnjatic
authors.forename: Y
authors.initials: Y
authors.lastname: Nagata
authors.forename: E
authors.initials: E
authors.lastname: Stockert
authors.forename: D L
authors.initials: DL
authors.lastname: Panicali
authors.forename: Y T
authors.initials: YT
authors.lastname: Chen
authors.forename: A
authors.initials: A
authors.lastname: Knuth
authors.forename: L J
authors.initials: LJ
authors.lastname: Old
authors.forename: V
authors.initials: V
authors.lastname: Cerundolo
mesh_terms: D019943:Amino Acid Substitution / Q000276:immunology; D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D003545:Cysteine / Q000276:immunology / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D015789:HLA-A2 Antigen / Q000378:metabolism; D006801:Humans; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D008545:Melanoma / Q000276:immunology / Q000473:pathology; D008565:Membrane Proteins; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000276:immunology* / Q000302:isolation & purification / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D011506:Proteins / Q000138:chemical synthesis / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D000951:Antigens, Neoplasm; C104948:CTAG1B protein, human; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D008565:Membrane Proteins; D010446:Peptide Fragments; D011506:Proteins; D003545:Cysteine