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Efficient Cross-Presentation by Heat Shock Protein 90-Peptide Complex-Loaded Dendritic Cells via an Endosomal Pathway

Takehiro Kurotaki^*,, Yasuaki Tamura^1,*, Gosei Ueda^*,, Jun Oura^*, Goro Kutomi^*, Yoshihiko Hirohashi^*, Hiroeki Sahara^*, Toshihiko Torigoe^*, Hiroyoshi Hiratsuka, Hajime Sunakawa, Koichi Hirata and Noriyuki Sato^*

^* Department of Pathology, School of Medicine, Sapporo Medical University, Sapporo, Japan; Department of Surgery, School of Medicine, Sapporo Medical University, Sapporo, Japan; and Department of Oral and Maxillofacial Surgery, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Yasuaki Tamura, Department of Pathology, School of Medicine, Sapporo Medical University, South 1, West 17, Chuo-ku, Sapporo 060-8556, Japan. E-mail address: ytamura{at}sapmed.ac.jp

² Abbreviations used in this paper: HSP, heat shock protein; DC, dendritic cell; BMDC, bone marrow-derived DC; VSV, vesicular stomatitis virus; 2M, 2 macroglobulin; SR-A, scavenger receptor A; ER, endoplasmic reticulum.