Identification and characterization of a human agonist cytotoxic T-lymphocyte epitope of human prostate-specific antigen

Clin Cancer Res. 2002 Jan;8(1):41-53.

Abstract

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.

MeSH terms

  • Animals
  • Apoptosis
  • Carcinoma / immunology
  • Cells, Cultured
  • Cytokines / metabolism
  • Cytotoxicity, Immunologic / drug effects
  • Dendritic Cells
  • Epitopes, T-Lymphocyte / genetics
  • Epitopes, T-Lymphocyte / immunology*
  • Flow Cytometry
  • HLA-A2 Antigen / immunology
  • HLA-A2 Antigen / metabolism*
  • Humans
  • Immunization
  • Immunodominant Epitopes / genetics
  • Immunodominant Epitopes / immunology*
  • Male
  • Mice
  • Mice, Transgenic
  • Oligopeptides / genetics
  • Oligopeptides / immunology*
  • Oligopeptides / metabolism
  • Prostate-Specific Antigen / genetics
  • Prostate-Specific Antigen / immunology*
  • Prostatic Neoplasms / immunology
  • Protein Binding
  • Recombination, Genetic / immunology
  • T-Lymphocytes, Cytotoxic / enzymology
  • T-Lymphocytes, Cytotoxic / immunology*
  • Vaccinia virus / genetics

Substances

  • Cytokines
  • Epitopes, T-Lymphocyte
  • HLA-A2 Antigen
  • Immunodominant Epitopes
  • Oligopeptides
  • Prostate-Specific Antigen