title: Immunogenicity of HLA-A1-restricted peptides derived from S100A4 (metastasin 1) in melanoma patients.
abstract: S100A4 (metastasin 1) belongs to the S100 family of Ca(2+) binding proteins. While not present in most differentiated adult tissues, S100A4 is upregulated in the micromilieu of tumors. It is primarily expressed by tumor-associated macrophages, fibroblasts, and tumor endothelial cells. Due to its strong induction in tumors S100A4 is a promising target for cancer immunotherapy. By reverse immunology, using epitope prediction programs, we identified 3 HLA-A1-restricted peptide epitopes (S100A4 A1-1, A1-2, and A1-3) which are subject to human T cell responses as detected in peripheral blood of melanoma patients by means of IFN-gamma ELISPOT and cytotoxicity assays. In addition, IFN-gamma responses to S100A4 A1-2 can not only be induced by stimulation of T cells with peptide-loaded DC but also by stimulation with S100A4 protein-loaded DC, indicating that this epitope is indeed generated by processing of the endogenously expressed protein. In addition, S100A4 A1-2 reactive T cells demonstrate lysis of HLA-A1(+) fibroblasts in comparison to HLA-A1(-) fibroblasts. In summary, this HLA-A1-restricted peptide epitope is a candidate for immunotherapeutical approaches targeting S100A4-expressing cells in the tumor stroma.
authors.affiliation: Department of Dermatology, Venerology and Allergology, University of Wuerzburg, Josef-Schneider-Strasse 2, Würzburg, Germany. Hofmeister_V@klinik.uni-wuerzburg.de
authors.forename: Valeska
authors.initials: V
authors.lastname: Hofmeister-Mueller
authors.forename: Claudia S
authors.initials: CS
authors.lastname: Vetter-Kauczok
authors.forename: Ramona
authors.initials: R
authors.lastname: Ullrich
authors.forename: Katharina
authors.initials: K
authors.lastname: Meder
authors.forename: Eugene
authors.initials: E
authors.lastname: Lukanidin
authors.forename: Eva-Bettina
authors.initials: EB
authors.lastname: Broecker
authors.forename: Per thor
authors.initials: Pt
authors.lastname: Straten
authors.forename: Mads Hald
authors.initials: MH
authors.lastname: Andersen
authors.forename: David
authors.initials: D
authors.lastname: Schrama
authors.forename: Juergen C
authors.initials: JC
authors.lastname: Becker
mesh_terms: D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D000939:Epitopes / Q000276:immunology* / Q000378:metabolism; D015788:HLA-A1 Antigen / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D008545:Melanoma / Q000276:immunology* / Q000473:pathology; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology*; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000276:immunology*; D016415:Sequence Alignment; D012878:Skin Neoplasms / Q000276:immunology* / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D000939:Epitopes; D015788:HLA-A1 Antigen; D010446:Peptide Fragments; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C077591:S100A4 protein, human; D007371:Interferon-gamma