Heat shock protein-mediated cell penetration and cytosolic delivery of macromolecules by a telomerase-derived peptide vaccine

Lee, Seoung Ae; Kim, Bo Ram; Kim, Bu Kyung; Kim, Dong Won; Shon, Won Jun; Lee, Na Rae; Kim, Bum Joon

doi:10.1016/j.biomaterials.2013.06.015

Cited by 35 publications

(38 citation statements)

References 40 publications

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“…Recently, a systematic cataloging of these peptides has been carried out, and various families have been described (45). GV1001, a hTERT-derived peptide, has been proposed as a CPP (46). However, in this study, GV1001 internalization required heat shock protein 70 or heat shock protein 90 interaction, whereas it was only weakly inhibited by heparin.…”

Section: Discussionmentioning

confidence: 49%

Heparan Sulfate Proteoglycans Promote Telomerase Internalization and MHC Class II Presentation on Dendritic Cells

Galaine

Kellermann

Guillaume

et al. 2016

The Journal of Immunology

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Telomerase is a prototype-shared tumor Ag and represents an attractive target for anticancer immunotherapy. We have previously described promiscuous and immunogenic HLA-DR–restricted peptides derived from human telomerase reverse transcriptase (hTERT) and referred as universal cancer peptide (UCP). In nonsmall cell lung cancer, the presence of spontaneous UCP-specific CD4 T cell responses increases the survival of chemotherapy-responding patients. However, the precise mechanisms of hTERT’s uptake, processing, and presentation on MHC-II molecules to stimulate CD4 T cells are poorly understood. In this work, by using well-characterized UCP-specific CD4 T cell clones, we showed that hTERT processing and presentation on MHC-II involve both classical endolysosomal and nonclassical cytosolic pathways. Furthermore, to our knowledge, we demonstrated for the first time that hTERT’s internalization by dendritic cells requires its interaction with surface heparan sulfate proteoglycans. Altogether, our findings provide a novel mechanism of tumor-specific CD4 T cell activation and will be useful for the development of novel cancer immunotherapies that harness CD4 T cells.

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Section: Discussionmentioning

confidence: 49%

Heparan Sulfate Proteoglycans Promote Telomerase Internalization and MHC Class II Presentation on Dendritic Cells

Galaine

Kellermann

Guillaume

et al. 2016

The Journal of Immunology

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“…An alternative concept for delivery to the cytosol was recently proposed. [28] Heat-shock protein (HSP) mediated endocytosis was shown to be responsible for internalization of a peptide developed as a cancer vaccine. Furthermore, due to the overexpression of HSPs in tumor cells, this approach suggests opportunities for targeting cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Towards Intracellular Delivery of Peptides

Marzinzik¹,

Vorherr

2013

Chimia

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In view of our more comprehensive understanding with respect to intracellular pathways and their regulation, a vast number of interesting drug targets appear to be in a space that can be addressed neither by small molecules nor by biologics. Especially, interference with intracellular protein-protein interactions, if successful, seems to offer considerable opportunities to expand the application of peptides as therapeutics, in particular in the field of oncology. This review focuses on requirements for the development of peptide therapeutics aiming at intracellular targets. In addition, an outlook for developments in this field based on recent examples for peptides active in cellular assays, highlighting key requirement to assess permeability, is provided.

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“…To address the issue of how GV1001 elicits a specific CTL response, we hypothesized that the peptide might be directly delivered into the cytosol via penetration of the cell membrane barrier, allowing access to the MHC class I molecules of antigen-presenting cells, particularly dendritic cells. The potential of GV1001 as a CPP molecule was examined using a Fluorescein isothiocyanate (FITC)-labeled peptide [19]. The labeled peptide was able to penetrate the cells used in our study in a concentration-dependent manner, irrespective of cell type, whether tumor cells (Huh7, MCF7, Raji, THP1, CHO, HepG2 and K562) or primary cells (mouse BMDCs and human PBMCs).…”

Section: Potential Of Gv1001 As a Heat Shock Protein (Hsp)-mediatementioning

confidence: 99%

“…GV1001 exhibits biological activities beyond its use as a cancer vaccine, including as an anti-inflammatory agent [14], as a direct anticancer drug [15], as an anti-apoptotic and antioxidant compound [16] and as an antiviral [17,18]. We recently reported that GV1001 is also a CPP [19]. In contrast to other CPPs, which penetrate the cell membrane through electrostatic interactions with proteoglycans, GV1001 permits the cytosolic delivery of macromolecules such as proteins, DNA and siRNA via extracellular heat shock protein 90 (eHSP90) and 70 (eHSP70) complexes [19].…”

Section: Introductionmentioning

confidence: 99%

“…We recently reported that GV1001 is also a CPP [19]. In contrast to other CPPs, which penetrate the cell membrane through electrostatic interactions with proteoglycans, GV1001 permits the cytosolic delivery of macromolecules such as proteins, DNA and siRNA via extracellular heat shock protein 90 (eHSP90) and 70 (eHSP70) complexes [19]. The eHSP-GV1001 complex may also have biological effects in addition to the cytosolic delivery function of GV1001.…”

Section: Introductionmentioning

confidence: 99%

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The Telomerase-Derived Anticancer Peptide Vaccine GV1001 as an Extracellular Heat Shock Protein-Mediated Cell-Penetrating Peptide

Kim

Seo

Lee

et al. 2016

IJMS

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Cell-penetrating peptides (CPPs), which can facilitate the transport of molecular cargo across the plasma membrane, have become important tools in promoting the cellular delivery of macromolecules. GV1001, a peptide derived from a reverse-transcriptase subunit of telomerase (hTERT) and developed as a vaccine against various cancers, reportedly has unexpected CPP properties. Unlike typical CPPs, such as the HIV-1 TAT peptide, GV1001 enabled the cytosolic delivery of macromolecules such as proteins, DNA and siRNA via extracellular heat shock protein 90 (eHSP90) and 70 (eHSP70) complexes. The eHSP-GV1001 interaction may have biological effects in addition to its cytosolic delivery function. GV1001 was originally designed as a major histocompatibility complex (MHC) class II-binding cancer epitope, but its CPP properties may contribute to its strong anti-cancer immune response relative to other telomerase peptide-based vaccines. Cell signaling via eHSP-GV1001 binding may lead to unexpected biological effects, such as direct anticancer or antiviral effects. In this review, we focus on the CPP effects of GV1001 bound to eHSP90 and eHSP70.

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Heat shock protein-mediated cell penetration and cytosolic delivery of macromolecules by a telomerase-derived peptide vaccine

Cited by 35 publications

References 40 publications

Heparan Sulfate Proteoglycans Promote Telomerase Internalization and MHC Class II Presentation on Dendritic Cells

Heparan Sulfate Proteoglycans Promote Telomerase Internalization and MHC Class II Presentation on Dendritic Cells

Towards Intracellular Delivery of Peptides

The Telomerase-Derived Anticancer Peptide Vaccine GV1001 as an Extracellular Heat Shock Protein-Mediated Cell-Penetrating Peptide

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