Identification of immunodominant HLA-B7-restricted CD8+ cytotoxic T cell epitopes derived from mammaglobin-A expressed on human breast cancers
- نوع فایل : کتاب
- زبان : انگلیسی
- مؤلف : Haseeb Ilias Basha Venkataswarup Tiriveedhi Timothy P. Fleming William E. Gillanders T. Mohanakumar
- چاپ و سال / کشور: 2010
Description
Mammaglobin-A (MGBA), a 10-kD protein, is over expressed in 80% of primary and metastatic human breast cancers. Breast cancer patients demonstrate high frequencies of CD8? cytotoxic T lymphocytes (CTL) specific to MGBA. Defining CD8? CTL responses to HLA class I-restricted MGBA-derived epitopes assumes significance in the context of our ongoing efforts to clinically translate vaccine strategies targeting MGBA for prevention and/or treatment of human breast cancers. In this study, we define the CD8? CTL response to MGBA-derived candidate epitopes presented in the context of HLA-B7, which has a frequency of 17.7% in Caucasian and 15.5% in African American populations. We identified seven MGBA-derived candidate epitopes with high predicted binding scores for HLA-B7 using a computer algorithm. Membrane stabilization studies with TAP-deficient T2 cells transfected with HLA-B7 indicated that MGBA B7.3 (VSKTEYKEL), B7.6 (KLLMVLMLA), B7.7 (NPQVSKTEY), and B7.1 (YAGSGCPLL) have the highest HLA-B7 binding affinities. Further, two CD8? CTL cell lines generated in vitro against T2.B7 cells individually loaded with MGBA-derived candidate epitopes showed significant cytotoxic activity against MGBA B7.1, B7.3, B7.6, and B7.7. In addition, the same CD8? CTL lines lysed the HLA-B7?/MGBA? human breast cancer cell line DU-4475 but had no significant cytotoxicity against HLA-B7- or MGBA- breast cancer cell lines. Cold-target inhibition studies strongly suggest that MGBA B7.3 is an immunodominant epitope. In summary, our results define HLA-B7-restriced, MGBA-derived, CD8? CTL epitopes with all of the necessary features for developing novel vaccine strategies against HLA-B7 expressing breast cancer patients.
Breast Cancer Res Treat (2011) 127:81–89 Received: 16 April 2010 / Accepted: 29 May 2010 / Published online: 11 June 2010 Springer Science+Business Media, LLC. 2010
