Specific Immunogenicity of Heat Shock Protein gp96 Derives from Chaperoned Antigenic Peptides and Not from Contaminating Proteins

Binder, Robert J.; Kelly, John; Vatner, Ralph; Srivastava, Pramod K.

doi:10.4049/jimmunol.179.11.7254

Cited by 41 publications

(32 citation statements)

References 33 publications

(42 reference statements)

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“…Consequently, gp96-peptide complexes extracted from cancer cells harbor tumor-specific peptides and are immunogenic, offering a tool for active immunization against the tumor (13)(14)(15)(16)(17). Therefore, immunologists speculate that every preparation of gp96-associated peptide pool is different.…”

Section: Resultsmentioning

confidence: 99%

Isolation and Identification of Renal Cell Carcinoma-Derived Peptides Associated with GP96

Zhang

et al. 2013

Technol Cancer Res Treat

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We determined the possible associated determinants and analyzed whether gp96-associated antigenic peptides can be found in renal cell carcinoma (RCC). The gp96-peptide complexes were chromatographically purified from resected tumor tissue of RCC patients. SDS-PAGE and Western blot analysis confirmed gp96 using the gp96 monoclonal antibody, and its con- are small molecular peptides, and the two peptides are deduced to be RCC-associated peptides. The identified peptides were confirmed to be associated with gp96 using the protocols described above. However, the specificity and relevance of the association to the immunogenicity of gp96 remains to be examined. Further analysis must be accomplished before the findings can be applied in peptide vaccine.

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Section: Resultsmentioning

confidence: 99%

Isolation and Identification of Renal Cell Carcinoma-Derived Peptides Associated with GP96

Zhang

et al. 2013

Technol Cancer Res Treat

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“…Also, gp96 regulates the activity of plasmacytoid dendritic cells via CD91 (38,39). The gp96 also enables specific immune responses by potentiating cross presentation of immunogenic peptides on MHC class I; thus, facilitating antigen specific activation of cytotoxic T cells (40)(41)(42)(43). A phase II trial is ongoing, in which patients are immunized with complexes of gp96 in combination with tumor antigens to promote presentation of these tumor-derived antigens by APC (44).…”

Section: Discussionmentioning

confidence: 99%

Peptides modulating conformational changes in secreted chaperones: From in silico design to preclinical proof of concept

Kliger

Levy

Oren

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Blocking conformational changes in biologically active proteins holds therapeutic promise. Inspired by the susceptibility of viral entry to inhibition by synthetic peptides that block the formation of helixhelix interactions in viral envelope proteins, we developed a computational approach for predicting interacting helices. Using this approach, which combines correlated mutations analysis and Fourier transform, we designed peptides that target gp96 and clusterin, 2 secreted chaperones known to shift between inactive and active conformations. In human blood mononuclear cells, the gp96-derived peptide inhibited the production of TNF␣, IL-1␤, IL-6, and IL-8 induced by endotoxin by >80%. When injected into mice, the peptide reduced circulating levels of endotoxin-induced TNF␣, IL-6, and IFN␥ by >50%. The clusterin-derived peptide arrested proliferation of several neoplastic cell lines, and significantly enhanced the cytostatic activity of taxol in vitro and in a xenograft model of lung cancer. Also, the predicted mode of action of the active peptides was experimentally verified. Both peptides bound to their parent proteins, and their biological activity was abolished in the presence of the peptides corresponding to the counterpart helices. These data demonstrate a previously uncharacterized method for rational design of protein antagonists.cancer ͉ contact map prediction ͉ cytokines ͉ inflammation ͉ helix C onformational changes in proteins have an essential role in regulating activity. Natural and synthetic molecules that modulate such changes are of considerable biological importance. Such molecules include allosteric effectors that alter the rate of enzymecatalyzed reactions (1), molecules that shift the oligomerization equilibrium of proteins (2), and molecules that interfere with transmembrane helix-helix associations (3).Conformational changes that have been extensively studied are those that take place during viral-induced membrane fusion. This process is required for the propagation of enveloped viruses, and is facilitated by viral encoded type 1 integral membrane proteins (4, 5). Viral entry of enveloped viruses depends on a conformational change involving the formation of helix-helix interactions, i.e., 2 alpha helices that do not interact in the native (nonfusogenic) state, but do interact with each other when the protein folds into its fusion-active (fusogenic) form. Remarkably, synthetic peptides corresponding to some of these helical segments have an antiviral activity (6 -8), of which one has been developed for the treatment of HIV-1 infection (9, 10).We hypothesized that such a mode of inhibition could be also applied on nonviral proteins. The aim of the present study was to develop a computational tool for the detection of intramolecular helix-helix interactions and to use this tool for detecting such interacting helices in proteins of interest. This study focuses on secreted chaperones due to their biological and therapeutic relevance (11-14), and because conformational changes are known to take p...

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“…Subsequently, they demonstrated that the specific immunogenicity of Gp96 preparations was due to MHC Class-I epitope precursors associated with Gp96 and not to contaminating b-galactosidase protein. 127 Furthermore, an extensive report convincingly underscores the intrinsic cell-signaling properties of the molecular chaperones. 128 However, some doubts remain whether the therapeutic immunological effects of Gp96 treatment, such as cytokine stimulation and CTL responses, are due to contamination with lipopolysaccharide or result from the HSPs themselves and/or the chaperoned peptides.…”

Section: Discovery Of Hsps Gp96 and Their Immunological Propertiesmentioning

confidence: 97%

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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Specific Immunogenicity of Heat Shock Protein gp96 Derives from Chaperoned Antigenic Peptides and Not from Contaminating Proteins

Cited by 41 publications

References 33 publications

Isolation and Identification of Renal Cell Carcinoma-Derived Peptides Associated with GP96

Isolation and Identification of Renal Cell Carcinoma-Derived Peptides Associated with GP96

Peptides modulating conformational changes in secreted chaperones: From in silico design to preclinical proof of concept

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

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