Identification and characterization of a human agonist cytotoxic T-lymphocyte epitope of human prostate-specific antigen.
One potential target of vaccine therapy for human prostate cancer is the prostate-specific antigen (PSA). One strategy to enhance the immunogenicity of a self-antigen such as PSA is to develop agonist epitopes that are potentially more immunogenic. The studies described here report the design and analysis of an agonist epitope designated PSA-3A ("A" for agonist) of the PSA-3 CTL epitope. Studies demonstrate that when compared with the native PSA-3 epitope, the PSA-3A agonist demonstrates enhanced binding to the MHC class I A2 allele as well as enhanced stability of the peptide-MHC complex. T-cell lines generated with either the PSA-3 or the PSA-3A peptide showed higher levels of lysis of targets pulsed with the PSA-3A peptide than those targets pulsed with the PSA-3 peptide; this was observed when both the concentration of peptide and the ratio of effector to target cells were titrated. T cells stimulated with dendritic cells (DCs) pulsed with PSA-3A peptide produced higher levels of IFN-gamma than did DCs pulsed with PSA-3 peptide; however, no increase in apoptosis was seen in T cells stimulated with the PSA-3A agonist compared with those stimulated with PSA-3. Human T-cell lines generated with the PSA-3A agonist had the ability to lyse human prostate carcinoma cells expressing native PSA in an MHC-restricted manner. Recombinant vaccinia viruses were also constructed that contained the entire PSA transgene with and without the single amino acid change that constitutes the PSA-3A epitope; DCs infected with the recombinant vector containing the agonist amino acid change within the entire PSA gene (designated rV-PSA-3A) were more effective than DCs infected with the rV-PSA vector in enhancing IFN-gamma production by T cells. Finally, the PSA-3A agonist was shown to induce higher levels of T-cell activation, compared with the PSA-3 peptide, in an in vivo model using HLA-A2.1/K(b) transgenic mice. These studies thus demonstrate the potential use of the PSA-3A agonist epitope in both peptide- and vector-mediated immunotherapy protocols for prostate cancer.
Terasawa
Hiroshi
H
Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
Tsang
Kwong-Yok
KY
Gulley
James
J
Arlen
Philip
P
Schlom
Jeffrey
J
D000818:Animals; D017209:Apoptosis; D002277:Carcinoma / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D003713:Dendritic Cells; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D005434:Flow Cytometry; D015789:HLA-A2 Antigen / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007114:Immunization; D016056:Immunodominant Epitopes / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009842:Oligopeptides / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000235:genetics / Q000276:immunology*; D011471:Prostatic Neoplasms / Q000276:immunology; D011485:Protein Binding; D011995:Recombination, Genetic / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000201:enzymology / Q000276:immunology*; D014616:Vaccinia virus / Q000235:genetics
D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D016056:Immunodominant Epitopes; D009842:Oligopeptides; D017430:Prostate-Specific Antigen