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

Kurotaki, Takehiro; Tamura, Yasuaki; G, Ueda; Oura, Jun; Kutomi, Goro; Hirohashi, Yoshihiko; Sahara, Hiroeki; Torigoe, Toshihiko; Hiratsuka, Hiroyoshi; Sunakawa, Hajime; Hirata, Koichi; Sato, Noriyuki

doi:10.4049/jimmunol.179.3.1803

Cited by 98 publications

(114 citation statements)

References 36 publications

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“…Antigenic peptide-bound HSP 70 and 90 family proteins are known to work as immune modulators that enhance the cross-priming pathway and enhance antitumor immunity (44)(45)(46)(47). In this study, we confirmed anti-DNAJB8 immunity with DNAJB8-immunized mouse spleen cells.…”

Section: Discussionsupporting

confidence: 68%

HSP DNAJB8 Controls Tumor-Initiating Ability in Renal Cancer Stem–like Cells

et al. 2012

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Cancer stem-like cells (CSC) are a small population of cancer cells with superior tumor initiating, self-renewal, and differentiation properties. In this study, we show that the cancer-testis antigen and HSP40 family member DNAJB8 contributes to the CSC phenotype in renal cell carcinoma (RCC). DNAJB8 overexpression increased the percentage of side population (SP) cells representing CSCs in RCC cells, enhancing their tumor-initiating ability. Conversely, attenuation of DNAJB8 decreased SP cells and reduced tumor-initiating ability. The utility of DNAJB8 as an immunologic target was established in DNA vaccination experiments. Compared with immunization with the tumor-associated antigen survivin, which was expressed in both CSCs and non-CSCs in RCC, immunization with Dnajb8 expression plasmids yielded stronger antitumor effects. Together, our findings suggest that DNAJB8 plays a role in CSC maintenance and that it offers a candidate for CSC-targeting immunotherapy in RCC.

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Section: Discussionsupporting

confidence: 68%

HSP DNAJB8 Controls Tumor-Initiating Ability in Renal Cancer Stem–like Cells

et al. 2012

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“…As others and as we have already demonstrated, heat shock treatment accelerates the loading of peptides onto the binding sites of ORP150 and other HSPs (22). As shown in Fig.…”

Section: Generation Of Orp150-peptide Complex In Vitromentioning

confidence: 70%

“…Extracellular HSP-Ag complexes, which are released from damaged tumor cells or virusinfected cells, are considered to be candidate Ag sources for crosspresentation. The pathway for cross-presentation has been shown to be comprised of two distinct intracellular routes, a proteasome-TAP-dependent pathway and an endosome-recycling pathway (22,39). Recent reports have identified the pathway wherein peptide exchange onto recycling MHC class I molecules occurs within early endosomal compartments (40).…”

Section: Discussionmentioning

confidence: 99%

“…However, the underlying mechanism for efficient cross-presentation, in particular how the HSP-Ag complex can enter the MHC class I pathway, is not well understood. Recently, we have demonstrated that extracellular Hsp90-peptide complexes are efficiently cross-presented via the endosome-recycling pathway (22). In this Hsp90-mediated cross-presentation, the receptor-dependent endocytosed Hsp90-peptide complex was transferred to the early endosome in which a cysteine protease such as cathepsin S processed the precursor peptide.…”

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confidence: 99%

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Targeting to Static Endosome Is Required for Efficient Cross-Presentation of Endoplasmic Reticulum-Resident Oxygen-Regulated Protein 150-Peptide Complexes

Kutomi

Tamura²,

Okuya

et al. 2009

The Journal of Immunology

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Heat shock proteins (HSPs) such as Hsp70, gp96, and Hsp90 have been shown to elicit intriguing, efficient CTL responses by cross-presentation via an as yet entirely unknown mechanism. Oxygen-regulated protein 150 (ORP150), also known as grp170, is an endoplasmic reticulum-resident HSP and is up-regulated by hypoxia. It has been demonstrated that ORP150 binds tumor-associated Ag peptides within cancer cells. Immunization with an ORP150-tumor Ag complex has been shown to generate tumor-specific CTLs. Most recently, it has been shown that exogenous ORP150 induces cross-presentation of a chaperoned Ag, thereby stimulating Ag-specific CTLs. However, the mechanism underlying this efficient cross-presentation is still unsolved. In this study, we show that the ORP150-precursor peptide complex can elicit CTL response through cross-presentation as well as the CD4+ T cell response by dendritic cells. Furthermore, we observed that the internalized ORP150-peptide complex, but not OVA protein, which was not cross-presented, was sorted to the Rab5+, EEA1+ static early endosome, followed by translocation to a recycling endosome, where the ORP150-chaperoned peptide was processed and bound to MHC class I molecules. Moreover, we observed that immunization of mice with ORP150-peptide complexes elicited strong peptide-specific CTLs and antitumor effects in vivo. Our data indicate that targeting of the Ag to a “static” early endosme by ORP150 is required for the efficient cross-presentation.

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“…Fractions of tumor lysates were tested in vivo and revealed the HSPs as sought-after tumor-rejection antigens. 2,37,38 They included Gp96, 2,[38][39][40] Hsp90, 39,41 Hsc70/Hsp70 39,42,43 as well as calreticulin, 44,45 Hsp110 and Grp170. [46][47][48] In the ensuing years, these chaperones were extensively studied and successfully applied in preclinical cancer vaccination approaches (Table 1).…”

Section: Discovery Of Hsps Gp96 and Their Immunological Propertiesmentioning

confidence: 99%

Active‐specific immunotherapy of human cancers with the heat shock protein Gp96—revisited

Randazzo

Terness

Opelz

et al. 2012

Intl Journal of Cancer

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The passive administration of specific antibodies that selectively target tumors is a well-known strategy in cancer treatment. Active immunotherapy using peptide vaccines, in contrast, is expected to induce specific, cytolytic T cells in the patient, which react against tumor antigens and destroy malignant cells. Although several concepts exist, the identification and low immunogenicity of tumor-specific peptides remain a serious problem. Heat shock proteins (HSPs), notably glycoprotein (Gp) 96, are of special interest, because they are able to take molecular peptide-fingerprints of the protein array characteristic for a particular cell. Association of Gp96 with peptides has been shown to be essential for crosspresentation and activation of T cells. Consequently, Gp96-peptide complexes extracted from cancer cells harbor the tumor-specific peptides and are immunogenic, thus offering a tool for active immunization against the tumor. Already, several immunotherapy studies of human cancers have been carried out, showing no severe adverse effects but unfortunately only limited improvement in the clinical outcome. Vitespen, a commercial HSP-peptide complex vaccine based on tumor-derived Gp96, seems to induce an improved overall survival for subsets of early stage melanoma and kidney cancer patients. The limited access to vaccine material derived from the autologous tumor requires the development of alternative protocols. Moreover, counteracting immunosuppressive mechanisms induced by the malignancy might further improve the efficacy of vaccinations. This review critically analyzes the current state of clinical immunotherapy with Gp96, with special attention to Vitespen.Heat shock proteins (HSPs) came to attention of immunologists, because they chaperone peptides and interact with antigen-presenting cells (APCs) in a specific manner. As molecular chaperones, HSPs are essential for maintaining cellular functions by preventing misfolding and aggregation of nascent polypeptides and by facilitating protein folding. This function has been described for every organism. 1In the 1980s, the potential importance of HSPs for tumor therapy emerged, when it was observed that preparations of certain HSPs isolated from cancer cells elicited immunity by capturing the antigenic fingerprint of a specific cancer, so that they could act as a vaccine against subsequent tumor challenge.2 Since then, the immunological properties of HSPs were studied intensively, particularly those of endoplasmic reticulum (ER)-resident HSPs glycoprotein (Gp)96 (Grp94)

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

Cited by 98 publications

References 36 publications

HSP DNAJB8 Controls Tumor-Initiating Ability in Renal Cancer Stem–like Cells

HSP DNAJB8 Controls Tumor-Initiating Ability in Renal Cancer Stem–like Cells

Targeting to Static Endosome Is Required for Efficient Cross-Presentation of Endoplasmic Reticulum-Resident Oxygen-Regulated Protein 150-Peptide Complexes

Active‐specific immunotherapy of human cancers with the heat shock protein Gp96—revisited

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