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
Document Type
Article
Publication Title
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.
First Page
800
Last Page
11
DOI
10.1002/cncr.24048
Publication Date
2-15-2009
Recommended Citation
Bellone, Stefania; Anfossi, Simone; O'Brien, Timothy J.; Cannon, Martin J.; Silasi, Dan-Arin; Azodi, Masoud; Schwartz, Peter E.; Rutherford, Thomas J.; Pecorelli, Sergio; and Santin, Alessandro D., "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" (2009). Obstetrics and Gynecology. 135.
https://scholar.bridgeporthospital.org/obgyn/135
Identifier
19117353 (pubmed); 10.1002/cncr.24048 (doi)