Immunogenicity of HLA-A1-restricted peptides derived from S100A4 (metastasin 1) in melanoma patients.
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.
Hofmeister-Mueller
Valeska
V
Department of Dermatology, Venerology and Allergology, University of Wuerzburg, Josef-Schneider-Strasse 2, Würzburg, Germany. Hofmeister_V@klinik.uni-wuerzburg.de
Vetter-Kauczok
Claudia S
CS
Ullrich
Ramona
R
Meder
Katharina
K
Lukanidin
Eugene
E
Broecker
Eva-Bettina
EB
Straten
Per thor
Pt
Andersen
Mads Hald
MH
Schrama
David
D
Becker
Juergen C
JC
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
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