International Immunology, Vol. 15, No. 6, pp. 751-763,
June 2003
© 2003 Japanese Society for Immunology
Naturally occurring peptides associated with HLA-A2 in ovarian cancer cell lines identified by mass spectrometry are targets of HLA-A2-restricted cytotoxic T cells
1 Upstate Inc., Charlottesville, VA 22903, USA 2 Large Scale Proteomics Corp., Rockville, MD 20876, USA 3 Department of Chemistry, University of Virginia, Charlottesville, VA 22903, USA 4 Department of Oncology and Pathology, Radiumhemmet, Karolinska Hospital, 17176 Stockholm, Sweden 5 Unit of Immunotherapy of Human Tumors, Istituto Nazionale Tumori, 20133 Milan, Italy 6 Present address: Medarex Inc., 519 Rt. 173 West, Bloomsbury, NJ 08804, USA 7 Present address: MDS Proteomics, Charlottesville, VA 22904, USA 8 Present address: Wyeth-Lederle Viral Vaccine Immunology, Pearl River, NY 10956, USA 9 Present address: IOMAI Corporation, Gaithersburg, MD 20878, USA
Correspondence to: V. Ramakrishna; E-mail: vramakrishna{at}medarex.com
Transmitting editor: H. L. Ploegh
Identifying naturally occurring peptides bound to HLA class I molecules recognized by HLA-restricted cytotoxic T lymphocytes (CTL) is both relevant and central to the development of effective immunotherapeutic strategies against cancer. Several cancer-related genes have been reported for ovarian cancer, but very few are known to be naturally processed T cell epitopes. In the present study we used mass spectrometry to identify 16 novel HLA-A2-bound peptides from HLA-A2+ ovarian cancer cell lines. All 16 peptides are derived from source proteins with diverse functions and marked homology to known proteins found in public databases. Synthetic peptide analogues of identified sequences were found to stabilize HLA-A2.1, albeit with varying affinities. The peptides were found to be antigenic in that a primary CD8+ CTL response could be elicited from normal donor blood. The CTL generated were not only peptide specific, but failed to recognize targets pulsed with control peptides. In addition, recognition of shared HLA-A2-restricted epitopes by these CTL is suggested by their reactivity with a subset of HLA-A2+ tumor lines and freshly isolated cancer cells or cell lines established from peritoneal ascites. These results were further corroborated by competitive inhibition of lysis of an otherwise susceptible cell line in the presence of cold peptide-pulsed targets. Furthermore, lack of recognition of several HLA-A2+ control cell lines or cells isolated from normal ovaries suggests that these peptides are cancer related. These findings broaden the list of CTL-defined antigens that could lead to the development of multi-epitope vaccines for the treatment of ovarian cancer.
Keywords: antigen, cytotoxic T lymphocyte, HLA-A2, mass spectrometry, ovarian carcinoma
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