Identification of MHC class II-restricted T-cell epitopes in prostate-specific membrane antigen

Abstract

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.