Identification of NY-ESO-1 peptide analogues capable of improved stimulation of tumor-reactive CTL.
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.
Chen
J L
JL
Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom.
Dunbar
P R
PR
Gileadi
U
U
Jäger
E
E
Gnjatic
S
S
Nagata
Y
Y
Stockert
E
E
Panicali
D L
DL
Chen
Y T
YT
Knuth
A
A
Old
L J
LJ
Cerundolo
V
V
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
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