Identification of MHC class II-restricted T-cell epitopes in prostate-specific membrane antigen.
An effective tumor vaccine may be required to induce both CTLs and T-helper (Th) responses against tumor-associated antigens. CD4+ Th cells that recognize MHC class II-restricted epitopes play a central role in the initiation and maintenance of antitumor immune responses. Prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancer and thus is a potential target for prostate cancer immunotherapy. In this study, we attempted to identify Th epitopes derived from PSMA for enhancing prostate cancer vaccine by eliciting PSMA-specific Th responses. We first screened a panel of six epitope peptide candidates selected with the TEPITOPE program and found that all six peptides induced peptide-specific T-cell proliferation from one or more donors with estimated T-cell precursor frequencies of 0-4.17 x 10(-6). We then established peptide-specific T-cell clones for five of these six peptides and demonstrated that the T-cell clone specific for the PSMA(459) epitope (NYTLRVDCTPLMYSL) can recognize processed antigens from recombinant PSMA proteins. The PSMA(459) peptide was found to induce CD4+ T-cell responses in healthy individuals and prostate cancer patients with different HLA-DR alleles. To test the potential clinical application, human HLA-DR4 transgenic mice were immunized with PSMA(459) peptide and we found that PSMA(459) peptide immunization activated T cells that specifically responded to antigenic peptides derived from PSMA proteins and PSMA-positive tumor. Thus, the naturally processed Th epitope PSMA(459) could be included in prostate tumor vaccines to enhance PSMA-specific CTL responses.
Schroers
Roland
R
Departments of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Shen
Lei
L
Rollins
Lisa
L
Xiao
Zhen
Z
Sonderstrup
Grete
G
Slawin
Kevin
K
Huang
Xue F
XF
Chen
Si-Yi
SY
D000483:Alleles; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D000954:Antigens, Surface / Q000737:chemistry*; D015704:CD4 Antigens / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002455:Cell Division; D002469:Cell Separation; D004305:Dose-Response Relationship, Drug; D000939:Epitopes / Q000737:chemistry; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry*; D005434:Flow Cytometry; D043425:Glutamate Carboxypeptidase II / Q000737:chemistry*; D006680:HLA Antigens / Q000737:chemistry; D000949:Histocompatibility Antigens Class II / Q000737:chemistry*; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010452:Peptide Biosynthesis; D010455:Peptides / Q000737:chemistry; D011994:Recombinant Proteins / Q000737:chemistry; D012680:Sensitivity and Specificity; D012984:Software; D013601:T-Lymphocytes / Q000166:cytology; D019076:Transgenes
D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D015704:CD4 Antigens; D000939:Epitopes; D018984:Epitopes, T-Lymphocyte; D006680:HLA Antigens; D000949:Histocompatibility Antigens Class II; D010455:Peptides; D011994:Recombinant Proteins; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II