Efficient cross-presentation by heat shock protein 90-peptide complex-loaded dendritic cells via an endosomal pathway.
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.
Kurotaki
Takehiro
T
Department of Pathology, School of Medicine, Sapporo Medical University, Sapporo, Japan.
Tamura
Yasuaki
Y
Ueda
Gosei
G
Oura
Jun
J
Kutomi
Goro
G
Hirohashi
Yoshihiko
Y
Sahara
Hiroeki
H
Torigoe
Toshihiko
T
Hiratsuka
Hiroyoshi
H
Sunakawa
Hajime
H
Hirata
Koichi
K
Sato
Noriyuki
N
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
D019496:Cancer Vaccines; D018841:HSP90 Heat-Shock Proteins; D015395:Histocompatibility Antigens Class I; D010446:Peptide Fragments