title: Tumor-derived heat shock protein 70 peptide complexes are cross-presented by human dendritic cells.
abstract: Our study demonstrates that tumor-derived heat shock protein (HSP)70 chaperones a tyrosinase peptide and mediates its transfer to human immature dendritic cells (DCs) by receptor-dependent uptake. Human tumor-derived HSP70 peptide complexes (HSP70-PC) thus have the immunogenic potential to instruct DCs to cross-present endogenously expressed, nonmutated, and tumor antigenic peptides that are shared among tumors of the melanocytic lineage for T cell recognition. T cell stimulation by HSP70-instructed DCs is dependent on the Ag bound to HSP70 in that only DCs incubated with HSP70-PC purified from tyrosinase-positive (HSP70-PC/tyr(+)) but not from tyrosinase-negative (HSP70-PC/tyr(-)) melanoma cells resulted in the specific activation of the HLA-A*0201-restricted tyrosinase peptide-specific cytotoxic T cell clone. HSP70-PC-mediated T cell stimulation is very efficient, delivering the tyrosinase peptide at concentrations as low as 30 ng/ml of HSP70-PC for T cell recognition. Receptor-dependent binding of HSP70-PC and active cell metabolism are prerequisites for MHC class I-restricted cross-presentation and T cell stimulation. T cell stimulation does not require external DC maturation signals (e.g., exogenously added TNF-alpha), suggesting that signaling DC maturation is an intrinsic property of the HSP70-PC itself and related to receptor-mediated binding. The cross-presentation of a shared human tumor Ag together with the exquisite efficacy are important new aspects for HSP70-based immunotherapy in clinical anti-cancer vaccination strategies, and suggest a potential extension of HSP70-based vaccination protocols from a patient-individual treatment modality to its use in an allogeneic setting.
authors.affiliation: Clinical Cooperation Group Hyperthermie, Institute of Molecular Immunology, GSF National Research Center for Environment and Health, 81377 Munich, Germany. noessner@gsf.de
authors.forename: Elfriede
authors.initials: E
authors.lastname: Noessner
authors.forename: Robert
authors.initials: R
authors.lastname: Gastpar
authors.forename: Valeria
authors.initials: V
authors.lastname: Milani
authors.forename: Anna
authors.initials: A
authors.lastname: Brandl
authors.forename: Peter J S
authors.initials: PJ
authors.lastname: Hutzler
authors.forename: Maria C
authors.initials: MC
authors.lastname: Kuppner
authors.forename: Miriam
authors.initials: M
authors.lastname: Roos
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kremmer
authors.forename: Alexzander
authors.initials: A
authors.lastname: Asea
authors.forename: Stuart K
authors.initials: SK
authors.lastname: Calderwood
authors.forename: Rolf D
authors.initials: RD
authors.lastname: Issels
mesh_terms: D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D002461:Cell Line, Transformed; D002462:Cell Membrane / Q000201:enzymology / Q000276:immunology; D002999:Clone Cells; D003713:Dendritic Cells / Q000166:cytology / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation; D046911:Macromolecular Substances; D008545:Melanoma / Q000201:enzymology / Q000276:immunology; D009000:Monocytes / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D014442:Monophenol Monooxygenase / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism; D009842:Oligopeptides / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D021381:Protein Transport / Q000276:immunology; D011971:Receptors, Immunologic / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014407:Tumor Cells, Cultured
chemical_list: D000951:Antigens, Neoplasm; D018840:HSP70 Heat-Shock Proteins; D015395:Histocompatibility Antigens Class I; D046911:Macromolecular Substances; D009842:Oligopeptides; D011971:Receptors, Immunologic; D014442:Monophenol Monooxygenase