Tumor-derived heat shock protein 70 peptide complexes are cross-presented by human dendritic cells

被引:198
作者
Noessner, E
Gastpar, R
Milani, V
Brandl, A
Hutzler, PJS
Kuppner, MC
Roos, M
Kremmer, E
Asea, A
Calderwood, SK
Issels, RD
机构
[1] Univ Munich, Clin Cooperat Grp Hyperthermie, Munich, Germany
[2] Univ Munich, Inst Mol Immunol, GSF Natl Res Ctr Environm & Hlth, Munich, Germany
[3] Univ Munich, Klinikum Grosshadern, Med Klin 3, Munich, Germany
[4] GSF Natl Res Ctr Environm & Hlth, Inst Pathol, Neuherberg, Germany
[5] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA
[6] Harvard Univ, Sch Med, Boston, MA 02115 USA
关键词
D O I
10.4049/jimmunol.169.10.5424
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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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收藏
页码:5424 / 5432
页数:9
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