title: Efficient cross-presentation by heat shock protein 90-peptide complex-loaded dendritic cells via an endosomal pathway.
abstract: It is well-established that heat shock proteins (HSPs)-peptides complexes elicit antitumor responses in prophylactic and therapeutic immunization protocols. HSPs such as gp96 and Hsp70 have been demonstrated to undergo receptor-mediated uptake by APCs with subsequent representation of the HSP-associated peptides to MHC class I molecules on APCs, facilitating efficient cross-presentation. On the contrary, despite its abundant expression among HSPs in the cytosol, the role of Hsp90 for the cross-presentation remains unknown. We show here that exogenous Hsp90-peptide complexes can gain access to the MHC class I presentation pathway and cause cross-presentation by bone marrow-derived dendritic cells. Interestingly, this presentation is TAP independent, and followed chloroquine, leupeptin-sensitive, as well as cathepsin S-dependent endosomal pathways. In addition, we show that Hsp90-chaperoned precursor peptides are processed and transferred onto MHC class I molecules in the endosomal compartment. Furthermore, we demonstrate that immunization with Hsp90-peptide complexes induce Ag-specific CD8(+) T cell responses and strong antitumor immunity in vivo. These findings have significant implications for the design of T cell-based cancer immunotherapy.
authors.affiliation: Department of Pathology, School of Medicine, Sapporo Medical University, Sapporo, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Kurotaki
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Tamura
authors.forename: Gosei
authors.initials: G
authors.lastname: Ueda
authors.forename: Jun
authors.initials: J
authors.lastname: Oura
authors.forename: Goro
authors.initials: G
authors.lastname: Kutomi
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Hirohashi
authors.forename: Hiroeki
authors.initials: H
authors.lastname: Sahara
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Torigoe
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Hiratsuka
authors.forename: Hajime
authors.initials: H
authors.lastname: Sunakawa
authors.forename: Koichi
authors.initials: K
authors.lastname: Hirata
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Sato
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D002999:Clone Cells; D045142:Cross-Priming / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D011992:Endosomes / Q000276:immunology* / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000276:immunology* / Q000378:metabolism; D021381:Protein Transport / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D013945:Thymoma / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control
chemical_list: D019496:Cancer Vaccines; D018841:HSP90 Heat-Shock Proteins; D015395:Histocompatibility Antigens Class I; D010446:Peptide Fragments