| Dendritic cell (DC) immunotherapy is an attractive alternative method for treatment of ovarian cancer patients to prevent recurrent disease. In the first phase of this project, we identified potential HLA class I-binding cytotoxic T lymphocyte (CTL) epitopes within a series of novel ovarian tumor antigens, including stratum corneum chymotryptic enzyme (SCCE) and hepsin. Using peptide-pulsed matured DC, we generated 11 peptide-specific HLA A2.1 restricted CTL lines and one HLA B27 restricted CTL that lysed peptide-pulsed targets. CTL specific for two peptides, SCCE 123-131 and hepsin 170-178, also recognized autologous targets expressing endogenous antigen. We further observed lysis of CaOV3 ovarian tumor cells by SCCE 123-131 and SCCE 5-13 peptide-specific CTL. In the second phase, we investigated strategies for induction of antigen-specific CD4+ T cell responses, which may be critically important for effective tumor immunity. Recombinant protein-pulsed DC failed to generate reproducible CD4 + and CD8+ T cell responses. We then identified a region of SCCE, 110--139, that incorporates the SCCE 123--131 CTL epitope and several potential HLA DR1, DR4, and DR7 binding epitopes. Dendritic cells loaded with SCCE 110--139 stimulated antigen specific CD4+ T cell responses from a donor that expressed DR1 and DR7, and also generated peptide-specific CD8+ CTL that were partially restricted to HLA A2.1 and recognized targets expressing endogenously processed and presented SCCE epitopes. We also generated SCCE-specific CD4+ T cell responses from a second donor that did not express HLA DR1, DR4 or DR7 molecules, suggesting that the SCCE 110--139 peptide contains multiple T cell epitopes and has the potential to stimulate CD4+ T cell responses from multiple donors, regardless of their individual HLA class II type. The combined ability of DC loaded with SCCE 110--139 to stimulate CD8+ CTL restricted by HLA A2.1 and other class I molecules, and also to stimulate CD4+ helper T cell responses from diverse HLA DR backgrounds, suggests that immunotherapy targeted at SCCE 110--139 would be applicable to a broad patient population. |
