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Identification of MHC Class II-restricted T-cell Epitopes in Prostate-specific Membrane Antigen¹

Center for Cell and Gene Therapy [R. S., L. S., L. R., X. F. H., S-Y. C.] and Departments of Molecular and Human Genetics [R. S., L. S., L. R., S-Y. C.], Urology [K. S.], and Pediatrics [X. F. H.], Baylor College of Medicine, Houston, Texas 77030; Eastern Virginia Medical School, Norfolk, Virginia 23507 [Z. X.]; and Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California 94305 [G. S.]

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 PSMA₄₅₉ epitope (NYTLRVDCTPLMYSL) can recognize processed antigens from recombinant PSMA proteins. The PSMA₄₅₉ 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 PSMA₄₅₉ peptide and we found that PSMA₄₅₉ 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 PSMA₄₅₉ could be included in prostate tumor vaccines to enhance PSMA-specific CTL responses.

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