Interaction of Heat Shock Proteins with Peptides and Antigen Presenting Cells: Chaperoning of the Innate and Adaptive Immune Responses

Srivastava, Pramod K.

doi:10.1146/annurev.immunol.20.100301.064801

Cited by 772 publications

(625 citation statements)

References 98 publications

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“…7 One of the best-characterized biological responses to fever is the induction of heat shock protein (HSP) expression. 8,9 HSPs have the promiscuous ability to chaperone and present a broad repertoire of tumor antigens to dendritic cells, and activate both innate and adaptive antitumor immune responses [10][11][12][13][14] and have been extensively tested in clinical trials. [15][16][17] For example, vaccination with autologous tumor-derived HSP gp96-peptide complexes (HSPPC-96), extracted from autologous resected tumors, has been shown to stimulate tumor antigen-specific immune responses in patients with renal cell carcinoma and melanoma in clinical studies.…”

Section: Introductionmentioning

confidence: 99%

A phase I trial of intratumoral administration of recombinant oncolytic adenovirus overexpressing HSP70 in advanced solid tumor patients

Li¹,

Liu

Xr³

et al. 2008

Gene Ther

105

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Our pre-clinical studies demonstrated that intratumoral vaccination with a recombinant oncolytic type 2 adenovirus overexpressing the heat shock protein (HSP)70 protein, designated as H103, can inhibit primary and metastatic tumors through enhanced oncolytic activity and HSPmediated immune responses against shared and mutated tumor antigens. In the pre-clinical studies of local H103 administration, no significant toxicity was observed in the animal trials with mice, cavy or rhesus monkeys. A phase I clinical trial of intratumoral injection of H103 was conducted in the patients with advanced solid tumors. A total of 27 patients were injected intratumorally with H103 in a dose-escalation study from a dose of 2.5 Â 10 7 to 3.0 Â 10 12 viral particles (VPs). The maximum tolerated dose of H103 was not defined. Two patients developed dose-limiting toxicities of grade III fever at the dose of 1.5 Â 10 12 VP and transient grade IV thrombocytopenia at the dose of 3.0 Â 10 12 VP. The common adverse events were mainly mild to moderate (grade I/II) in nature, including fever, mild injection-site reaction, leucopenia, lymphopenia, thrombocytopenia and hypochromia. The objective response (complete response+partial response) to H103-injected tumors was 11.1% (3/27), and the clinical benefit rate (complete response+partial response+minor response+stable disease) was 48.1%. Interestingly, transient and partial regression of distant, uninjected tumors was observed in three patients. The numbers of immune cells (CD4 + and CD8 + T cells, and natural killer cells) were elevated after H103 administration, but without statistical significance. This phase I trial demonstrates that intratumoral administration of H103 can be safely applied to cancer patients and shows promising clinical antitumor activity, warranting a further clinical investigation.

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Section: Introductionmentioning

confidence: 99%

A phase I trial of intratumoral administration of recombinant oncolytic adenovirus overexpressing HSP70 in advanced solid tumor patients

Li¹,

Liu

Xr³

et al. 2008

Gene Ther

105

View full text Add to dashboard Cite

show abstract

“…The ability of HSP to facilitate the cross-presentation of MHC class I-restricted epitopes and to prime CD8 + cell effector responses has been well established [11]. Mammalian HSP such as the human cytosolic 70-kDa HSP (Hsp70) or gp96 are able to form highly immunogenic HSP:peptide complexes and to elicit antigen-specific CD8 + T cell responses to the chaperoned peptides [8,9].…”

Section: Introductionmentioning

confidence: 99%

The heat shock protein Hsp70 enhances antigen-specific proliferation of human CD4+ memory T cells

et al. 2005

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Heat shock proteins (HSP) can interact with a wide variety of peptides and the resulting HSP:peptide complexes are known to be highly immunogenic. The ability of HSP:peptide complexes to elicit CD8 + T cell responses by cross-presentation of exogenous antigen via MHC class I is well known. In contrast, their role in the activation of CD4 + T cells is less clearly defined, although several recent studies in mice and T cell lines suggest an involvement of HSP in the presentation of antigenic peptides via MHC class II. In this study we have investigated the potential of antigenic peptides from tetanus toxin and influenza hemagglutinin complexed to the human stress-inducible Hsp70 to enhance activation and proliferation of human memory CD4 + T cells. Hsp70:peptide complexes were found to amplify the proliferation of antigen-specific CD4 + T cells as confirmed by HLA-DR tetramer staining. Complex formation of the antigenic peptide with Hsp70 was absolutely required to elicit an antigen-specific amplification. This effect was most pronounced at low doses of antigen and decreasing APC/CD4 + T cell ratios. Taken together, we show the potential of Hsp70 to enhance antigen-specific CD4 + T cell proliferation and to increase the immunogenicity of presented peptides in human CD4 + T cells.

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“…Numerous studies have evaluated tumour-derived HSPs, including glucose regulated protein (GRP) 94 (gp96, HSP96) and HSP70, for immunotherapy [25]. Although the focus was initially on the induction of CTL responses, it has been noticed that NK cell depletion can also abrogate the efficacy of immunization with gp96 or HSP70 [26].…”

Section: Discussionmentioning

confidence: 99%

“…HSP70 might either act directly on NK cells, e.g. via C-type lectin NK receptors [21, 42], or on other cells which express HSP receptors [25] and cross-talk to NK cells, e.g. DCs [7].…”

Section: Discussionmentioning

confidence: 99%

The endogenous danger signals HSP70 and MICA cooperate in the activation of cytotoxic effector functions of NK cells

Elsner

Flügge

Lozano

et al. 2010

J Cellular Molecular Medi

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Although natural killer (NK) cells are often described as first line defence against infected or malignant cells which act without the need of prior activation, it is known now that the NK cell activity is tightly regulated by other cells and soluble factors. We show here that the stress-inducible heat shock protein (HSP) 70 activates human NK cells to kill target cells expressing major histocompatibility complex class I chain-related molecule A (MICA) in a natural killer group 2 member D (NKG2D-) dependent manner. The HSP70-derived peptide TKD (TKDNNLLGRFELSG) was able to replace the full-length HSP70 and to exert the same function. Interestingly, the expression of the cytotoxic effector protease granzyme B in NK cells was increased after TKD stimulation. When MICA and MICB expression was induced in human tumour cells by a histone deacetylase inhibitor and NK cells were activated by HSP70 or TKD, both treatments jointly improved the killing of the tumour cells. Thus, the synergistic activity of two stress-inducible immunological danger signals, HSP70 and MICA/B, leads to activation and enhanced cytotoxicity of human NK cells against tumour cells.

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Interaction of Heat Shock Proteins with Peptides and Antigen Presenting Cells: Chaperoning of the Innate and Adaptive Immune Responses

Cited by 772 publications

References 98 publications

A phase I trial of intratumoral administration of recombinant oncolytic adenovirus overexpressing HSP70 in advanced solid tumor patients

A phase I trial of intratumoral administration of recombinant oncolytic adenovirus overexpressing HSP70 in advanced solid tumor patients

The heat shock protein Hsp70 enhances antigen-specific proliferation of human CD4+ memory T cells

The endogenous danger signals HSP70 and MICA cooperate in the activation of cytotoxic effector functions of NK cells

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