Induction of Tc2 cells with specificity for prostate-specific antigen from patients with hormone-refractory prostate cancer

Abstract

Prostate-specific antigen (PSA) is a potentially useful antigen for targeted T-cell immunotherapy of prostate cancer (CaP). Our laboratory has identified a synthetic nonamer peptide (PSA 146–154) homologue of PSA, which binds to the prevalent human leukocyte antigen, HLA-Aff2, and elicits specific cytotoxic T-lymphocyte (CTL) responses from normal individuals of the HLA-Aff2 phenotype. In the present study, we report on the induction of CTL from peripheral blood mononuclear cells (PBMC) of patients with hormone-refractory CaP, which exhibit the same specificity. T-cell lines were established from two patients by stimulation of PBMC with PSA 146–154 peptide in vitro. The T-cell lines exhibited specific cytolytic activity against T2 cells pulsed with PSA 146–154 peptide, but not a control HLA-Aff2 binding peptide (HIV-RT 476–484) via chromium release assay (CRA). The T-cell lines also showed PSA 146–154 peptide-specific IL-4 responses, but no detectable interferon-gamma (IFN-γ) responses via enzyme-linked immuno-spot assays. Magnetic immuno-selection studies of one of the T-cell lines demonstrated that both cytolytic and interleukin-4 (IL-4) responses were mediated by CD8⁺, but not by CD4⁺ T cells. This Tc2 line was further characterized for the ability to recognize endogenously processed PSA epitopes. The line specifically secreted IL-4 in response to HLA-Aff2⁺ target cells transfected to express PSA and specifically lysed the PSA⁺ target cells, but not control transfected cells. The results indicate that the PSA 146–154 peptide emulates a naturally processed and presented peptide epitope of PSA that is within the T-cell repertoire of HLA-Aff2⁺ patients with CaP.