Identification of a Novel Immunogenic HLA-A*0201-Binding Epitope of HER-2/neu with Potent Antitumor Properties
| Autor: | Sonia A. Perez, Panagiota A. Sotiropoulou, Michael Papamichail, Constantin N. Baxevanis, Eftychia Lekka, Ioannis Missitzis, Angelos D. Gritzapis, Ioannis F. Voutsas, Nikolaos Tsavaris |
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| Rok vydání: | 2008 |
| Předmět: |
Receptor
ErbB-2 medicine.medical_treatment Immunology Breast Neoplasms Biology Cancer Vaccines Epitope Epitopes Mice Cell Line Tumor HLA-A2 Antigen MHC class I medicine Animals Humans Immunology and Allergy HLA-A Antigens Degranulation Immunotherapy Xenograft Model Antitumor Assays Molecular biology In vitro CTL Cell culture Disease Progression biology.protein CD8 Protein Binding T-Lymphocytes Cytotoxic |
| Zdroj: | The Journal of Immunology. 181:146-154 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | HER-2/neu oncoprotein is overexpressed in a variety of human tumors and is associated with aggressive disease. Immunogenic HER-2/neu CTL epitopes have been used as vaccines for the treatment of HER-2/neu positive malignancies with limited success. By applying prediction algorithms for MHC class I ligands and proteosomal cleavages, in this study, we describe the identification of HER-2/neu decamer LIAHNQVRQV spanning residues 85–94 (HER-2(1085)). HER-2(1085) proved to bind with high affinity to HLA-A2.1 and was stable for 4 h in an off-kinetics assay. This peptide was immunogenic in HLA-A2.1 transgenic (HHD) mice inducing peptide-specific CTL, which responded to tumor cell lines of various origin coexpressing human HER-2/neu and HLA-A2.1. This demonstrates that HER-2(1085) is naturally processed from endogenous HER-2/neu. Five of sixteen HER-2/neu+ HLA-A2.1+ breast cancer patients analyzed had HER-2(1085)-reactive T cells ranging from 0.35–0.70% of CD8+ T cells. Depletion of T regulatory cells from PBMC enabled the rapid expansion of HLA-A2.1/HER-2(1085)pentamer+/CD8+ cells (PENT+/CD8+), whereas significantly lower numbers of CTL could be generated from unfractionated PBMC. HER-2(1085)-specific human CTL recognized the HER-2/neu+ HLA-A2.1+ tumor cell line SKBR3.A2, as determined by IFN-γ intracellular staining and in the high sensitivity CD107α degranulation assay. Finally, HER-2(1085) significantly prolonged the survival of HHD mice inoculated with the transplantable ALC.A2.1.HER tumor both in prophylactic and therapeutic settings. These data demonstrate that HER-2(1085) is an immunogenic peptide, capable of eliciting CD8-mediated responses in vitro and in vivo, providing the platform for further exploitation of HER-2(1085) as a possible target for anticancer immunotherapy. |
| Databáze: | OpenAIRE |
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