Τίτλος:
Identification of a novel immunogenic HLA-A*0201-binding epitope of HER-2/neu with potent antitumor properties
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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 A1HC class I ligands and proteosomal cleavages, in this study, we describe the identification of HER-2/new 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(10 85)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. Copyright © 2008 by The American Association of Immunologists, Inc.
Συγγραφείς:
Gritzapis, A.D.
Voutsas, I.F.
Lekka, E.
Tsavaris, N.
Missitzis, I.
Sotiropoulou, P.
Perez, S.
Papamichail, M.
Baxevanis, C.N.
Περιοδικό:
Journal of Immunological Methods
Εκδότης:
American Association of Immunologists
Λέξεις-κλειδιά:
cancer vaccine; CD8 antigen; epidermal growth factor receptor 2; HER 2 leucylisoleucylalanylhistidylasparaginylglutaminylvalylarginylglutaminylvaline; HLA A2 antigen; peptide vaccine; unclassified drug; cancer vaccine; epidermal growth factor receptor 2; epitope; HLA A antigen; HLA A*0201 antigen; HLA-A*0201 antigen, animal experiment; animal model; antigen binding; antineoplastic activity; article; breast cancer; cancer immunotherapy; cytotoxic T lymphocyte; drug targeting; human; human cell; immunogenicity; mouse; nonhuman; oncogene neu; peripheral blood mononuclear cell; priority journal; transgenic mouse; animal; breast tumor; disease course; drug screening; genetics; immunology; metabolism; pathology; protein binding; tumor cell line, Animals; Breast Neoplasms; Cancer Vaccines; Cell Line, Tumor; Disease Progression; Epitopes; HLA-A Antigens; Humans; Mice; Protein Binding; Receptor, erbB-2; T-Lymphocytes, Cytotoxic; Xenograft Model Antitumor Assays
DOI:
10.4049/jimmunol.181.1.146
