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.

Abstract

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-gamma 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.

• Authors: Stefania Bellone, Simone Anfossi, Timothy J O'Brien, Martin J Cannon, Dan-Arin Silasi, Masoud Azodi, Peter E Schwartz, Thomas J Rutherford, Sergio Pecorelli, Alessandro D Santin
• Journal: Cancer (Cancer) Vol. 115 Issue 4 Pg. 800-11 (Feb 15 2009) ISSN: 0008-543X [Print] United States
• PMID: 19117353 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: (c) 2008 American Cancer Society.

Chemical References

• Antibodies, Monoclonal
• Cytokines
• HLA-A2 Antigen
• Peptide Fragments
• Serine Endopeptidases
• TADG-12 serine protease

Topics

• Aged
• Antibodies, Monoclonal (pharmacology)
• Antigen Presentation
• CD8-Positive T-Lymphocytes (cytology, immunology)
• Cell Line
• Cystadenocarcinoma, Serous (immunology, pathology)
• Cytokines (metabolism)
• Dendritic Cells (cytology, immunology)
• Female
• Flow Cytometry
• HLA-A2 Antigen (immunology)
• Humans
• Middle Aged
• Ovarian Neoplasms (immunology, pathology)
• Ovary (cytology, immunology)
• Peptide Fragments (immunology, metabolism)
• Serine Endopeptidases (genetics, immunology)
• T-Lymphocytes, Cytotoxic (immunology)