Screening of HLA-A24-restricted epitope peptides from prostate-specific membrane antigen that induce specific antitumor cytotoxic T lymphocytes.
OBJECTIVE
Prostate-specific membrane antigen (PSMA), which is a transmembrane glycoprotein predominantly expressed in prostate cancer, is an attractive target for tumor-specific immunotherapy. To identify human leukocyte antigen (HLA)-A24-restricted epitope peptides from PSMA for further application of the dendritic cell (DC)-based immunotherapy targeting prostate cancer, we have screened several PSMA-encoded HLA-A24-binding peptides for their capabilities to elicit specific antitumor CTL response in vitro.


METHODS
The amino acid sequence of PSMA was screened for peptides consisting of 9 or 10 amino acids, which possess the known HLA-A24-binding motif. Nine candidate peptides were screened for binding to HLA-A24 molecules. Then, each of these nine peptides was studied to determine whether CTL responses could be induced by primary in vitro immunization of CD8(+) T cells using peptide-pulsed autologous DCs derived from peripheral blood mononuclear cells of HLA-A24(+) healthy donor as antigen-presenting cells. The antigen specificity of the CTL lines was confirmed using several tumor cell lines as target cells, which were genetically modified to express both HLA-A24 and PSMA.


RESULTS
Two peptides, LYSDPADYF and NYARTEDFF, were demonstrated to elicit CTL lines that lyse peptide-pulsed, HLA-A24(+) B-lymphoblastoid cells. Each of the CTL lines recognized their specific PSMA-expressing target cells in a HLA-A24-restricted manner. The capability to release IFN-gamma by the CTL lines was specifically inhibited by anti-MHC class I and anti-CD8 monoclonal antibodies but not by anti-MHC class II and anti-CD4 monoclonal antibodies.


CONCLUSIONS
Two novel HLA-A24-restricted PSMA-derived epitopes were identified in this study. These epitopes can be used to further evaluate the clinical utility of DC-based immunotherapeutic strategies for treatment of hormone-refractory prostate cancers.
Horiguchi
Yutaka
Y
Department of Urology, School of Medicine, Keio University, Tokyo 160-8582, Japan.
Nukaya
Ikuei
I
Okazawa
Kazuhide
K
Kawashima
Ichiro
I
Fikes
John
J
Sette
Allesandro
A
Tachibana
Masaaki
M
Takesako
Kazutoh
K
Murai
Masaru
M
D000938:Antigen-Presenting Cells / Q000276:immunology; D000951:Antigens, Neoplasm / Q000737:chemistry* / Q000276:immunology*; D000954:Antigens, Surface; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002268:Carboxypeptidases / Q000737:chemistry*; D003602:Cytotoxicity, Immunologic; D000939:Epitopes / Q000494:pharmacology*; D043425:Glutamate Carboxypeptidase II; D015234:HLA-A Antigens / Q000378:metabolism*; D059871:HLA-A24 Antigen; D006801:Humans; D007167:Immunotherapy; D007371:Interferon-gamma / Q000494:pharmacology; D016393:Lymphoma, B-Cell / Q000276:immunology; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000628:therapy; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000276:immunology
D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D000939:Epitopes; D015234:HLA-A Antigens; D059871:HLA-A24 Antigen; D009842:Oligopeptides; D007371:Interferon-gamma; D002268:Carboxypeptidases; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II