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: J L Chen, P R Dunbar, U Gileadi, E Jäger, S Gnjatic, Y Nagata, E Stockert, D L Panicali, Y T Chen, A Knuth, L J Old, V Cerundolo
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 165 Issue 2 Pg. 948-55 (Jul 15 2000) ISSN: 0022-1767 [Print] United States
• PMID: 10878370 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Neoplasm
• CTAG1B protein, human
• Epitopes, T-Lymphocyte
• HLA-A2 Antigen
• Membrane Proteins
• Peptide Fragments
• Proteins
• Cysteine

Topics

• Amino Acid Substitution (immunology)
• Antigen Presentation
• Antigens, Neoplasm (chemistry, immunology, metabolism)
• Cysteine (immunology, metabolism)
• Cytotoxicity, Immunologic
• Epitopes, T-Lymphocyte (immunology)
• HLA-A2 Antigen (metabolism)
• Humans
• Intracellular Fluid (immunology, metabolism)
• Lymphocyte Activation (immunology)
• Melanoma (immunology, pathology)
• Membrane Proteins
• Peptide Fragments (chemical synthesis, immunology, isolation & purification, metabolism)
• Protein Binding (immunology)
• Proteins (chemical synthesis, immunology, metabolism)
• T-Lymphocytes, Cytotoxic (immunology, metabolism, pathology)
• Tumor Cells, Cultured