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-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.
Bellone
Stefania
S
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520-8063, USA.
Anfossi
Simone
S
O'Brien
Timothy J
TJ
Cannon
Martin J
MJ
Silasi
Dan-Arin
DA
Azodi
Masoud
M
Schwartz
Peter E
PE
Rutherford
Thomas J
TJ
Pecorelli
Sergio
S
Santin
Alessandro D
AD
D000368:Aged; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017951:Antigen Presentation; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D002460:Cell Line; D018284:Cystadenocarcinoma, Serous / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D015789:HLA-A2 Antigen / Q000276:immunology*; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000473:pathology; D010053:Ovary / Q000166:cytology / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D000911:Antibodies, Monoclonal; D016207:Cytokines; D015789:HLA-A2 Antigen; D010446:Peptide Fragments; D012697:Serine Endopeptidases; C417724:TADG-12 serine protease