Induction of human tumor‐associated differentially expressed gene‐12 (TADG‐12/TMPRSS3)‐specific cytotoxic T lymphocytes in human lymphocyte antigen‐A2.1–positive healthy donors and patients with advanced ovarian cancer

BACKGROUND:

Tumor‐associated differentially expressed gene‐12 (TADG‐12) is a serine protease recently found highly differentially expressed in epithelial ovarian cancer. The goal of this study was to identify potential immunogenic peptides derived from TADG‐12 for immunotherapy of ovarian carcinoma.

METHODS:

A bioinformatics approach (ie, the BIMAS algorithm, National Institutes of Health, http://bimas.dcrt.nih.gov/molbio/hla_bind ) was used to identify multiple immunogenic peptides derived from TADG‐12 that bind to human leukocyte antigen‐A2.1 and elicit peptide‐specific human cytotoxic T lymphocyte (CTL) responses in healthy individuals and in patients with advanced stage ovarian cancer.

RESULTS:

CD8+ CTL populations generated against 5 TADG‐12–derived peptides were consistently able to induce lysis of autologous peptide‐loaded target cells above background. Importantly, TADG‐12 YLPKSWTIQV peptide‐specific CTLs from healthy donors and ovarian cancer patients were found to effectively kill ovarian cancer cells naturally expressing TADG‐12. Cytotoxicity was significantly inhibited by anti–human lymphocyte antigen (HLA)‐A2.1 (BB7‐2) and anti–HLA class I (W6 of 32) monoclonal antibodies, whereas natural killer–sensitive K562 cells were not lysed. TADG‐12 YLPKSWTIQV peptide‐specific CTL precursor frequency was low in peripheral blood leukocytes of normal donors and ovarian cancer patients, as determined by interferon‐γ production in enzyme‐linked immunosorbent spot‐forming cell assays. Intracellular cytokine expression measured by flow cytometry after OKT‐3 monoclonal antibody stimulation showed a type 1 cytokine profile in YLPKSWTIQV peptide‐specific CTLs.

CONCLUSIONS:

The TADG‐12 YLPKSWTIQV peptide is an immunogenic epitope in ovarian tumors and may represent an attractive target for immunotherapy of ovarian cancer. These data may pave the way for TADG‐12 peptide‐derived cell‐based therapy, including dendritic cell immunotherapy, for the vaccination of ovarian cancer patients harboring chemotherapy‐resistant or residual disease. Cancer 2009. © 2008 American Cancer Society.