Please use this identifier to cite or link to this item:
http://doi.org/10.25358/openscience-7976
Authors: | Trojandt, Stefanie Reske-Kunz, Angelika B. Bros, Matthias |
Title: | Geldanamycin-mediated inhibition of heat shock protein 90 partially activates dendritic cells, but interferes with their full maturation, accompanied by impaired upregulation of RelB |
Online publication date: | 13-Oct-2022 |
Year of first publication: | 2014 |
Language: | english |
Abstract: | BACKGROUND: The chaperon heat shock protein 90 (HSP90) constitutes an important target for anti-tumor therapy due to its essential role in the stabilization of oncogenes. However, HSP90 is ubiquitously active to orchestrate protein turnover, chemotherapeutics that target HSP90 may affect immune cells as a significant side effect. Therefore, we asked for potential effects of pharmacological HSP90 inhibition at a therapeutically relevant concentration on human dendritic cells (DCs) as main inducers of both cellular and humoral immune responses, and on human CD4(+) T cells as directly activated by DCs and essential to confer B cell help. METHODS: Unstimulated human monocyte-derived DCs (MO-DCs) were treated with the prototypical HSP90 inhibitor geldanamycin (GA). Based on dose titration studies performed to assess cytotoxic effects, GA was applied at a rather low concentration, comparable to serum levels of clinically used HSP90 inhibitors. The immuno-phenotype (surface markers, cytokines), migratory capacity, allo T cell stimulatory and polarizing properties (proliferation, cytokine pattern) of GA-treated MO-DCs were assessed. Moreover, effects of GA on resting and differentially stimulated CD4(+) T cells in terms of cytotoxicity and proliferation were analysed. RESULTS: GA induced partial activation of unstimulated MO-DCs. In contrast, when coapplied in the course of MO-DC stimulation, GA prevented the acquisition of a fully mature DC phenotype. Consequently, this MO-DC population exerted lower allo CD4(+) T cell stimulation and cytokine production. Furthermore, GA exerted no cytotoxic effect on resting T cells, but abrogated proliferation of T cells stimulated by MO-DCs at either state of activation or by stimulatory antibodies. CONCLUSION: HSP90 inhibitors at clinically relevant concentrations may modulate adaptive immune responses both on the level of DC activation and T cell proliferation. Surprisingly, unstimulated DCs may be partially activated by that agent. However, due to the potent detrimental effects of HSP90 inhibitors on stimulated CD4(+) T cells, as an outcome a patients T cell responses might be impaired. Therefore, HSP90 inhibitors most probably are not suitable for treatment in combination with immunotherapeutic approaches aimed to induce DC/T cell activation. |
DDC: | 610 Medizin 610 Medical sciences |
Institution: | Johannes Gutenberg-Universität Mainz |
Department: | FB 04 Medizin |
Place: | Mainz |
ROR: | https://ror.org/023b0x485 |
DOI: | http://doi.org/10.25358/openscience-7976 |
Version: | Published version |
Publication type: | Zeitschriftenaufsatz |
License: | CC BY |
Information on rights of use: | https://creativecommons.org/licenses/by/2.0/ |
Journal: | Journal of experimental & clinical cancer research 33 |
Pages or article number: | Art. 16 |
Publisher: | BioMed central |
Publisher place: | London |
Issue date: | 2014 |
ISSN: | 1756-9966 0392-9078 |
Publisher URL: | http://dx.doi.org/10.1186/1756-9966-33-16 |
Publisher DOI: | 10.1186/1756-9966-33-16 |
Appears in collections: | DFG-OA-Publizieren (2012 - 2017) |
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![]() | geldanamycinmediated_inhibiti-20220925155625446.pdf | 1.15 MB | Adobe PDF | View/Open |