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Tumor-Derived Heat Shock Protein 70 Peptide Complexes Are Cross-Presented by Human Dendritic Cells.
J. Immunol. 169, 5424-5432 (2002)
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.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
CYTOTOXIC T-LYMPHOCYTES; RECEPTOR-MEDIATED ENDOCYTOSIS; GP96 INDUCES MATURATION; NATURAL-KILLER-CELLS; MELANOMA-CELLS; CUTTING EDGE; IN-VIVO; CHAPERONED PEPTIDES; ANTITUMOR IMMUNITY; STRESS PROTEINS
ISSN (print) / ISBN
0022-1767
e-ISSN
1550-6606
Journal
Journal of Immunology
Quellenangaben
Volume: 169,
Pages: 5424-5432
Publisher
American Association of Immunologists
Non-patent literature
Publications
Reviewing status
Peer reviewed