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Inhibitors of the Actin-Bundling Protein Fascin-1 Developed for Tumor Therapy Attenuate the T-Cell Stimulatory Properties of Dendritic Cells
SIMPLE SUMMARY: Expression of the actin-bundling protein Fascin-1 (Fscn1) is largely restricted to neuronal cells and to activated dendritic cells (DCs). DCs are important inducers of (antitumor) immune responses. In tumor cells, de novo expression of Fscn-1 correlates with their invasive and metast...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9179534/ https://www.ncbi.nlm.nih.gov/pubmed/35681718 http://dx.doi.org/10.3390/cancers14112738 |
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author | Zeyn, Yanira Harms, Gregory Tubbe, Ingrid Montermann, Evelyn Röhrig, Nadine Hartmann, Maike Grabbe, Stephan Bros, Matthias |
author_facet | Zeyn, Yanira Harms, Gregory Tubbe, Ingrid Montermann, Evelyn Röhrig, Nadine Hartmann, Maike Grabbe, Stephan Bros, Matthias |
author_sort | Zeyn, Yanira |
collection | PubMed |
description | SIMPLE SUMMARY: Expression of the actin-bundling protein Fascin-1 (Fscn1) is largely restricted to neuronal cells and to activated dendritic cells (DCs). DCs are important inducers of (antitumor) immune responses. In tumor cells, de novo expression of Fscn-1 correlates with their invasive and metastatic activities. Pharmacological Fscn1 inhibitors, which are currently under clinical trials for tumor therapy, were demonstrated to counteract tumor metastasis. Within this study, we were interested in better understanding the effects of Fscn1 inhibitors on DCs and discovered that two distinct Fascin-1 inhibitors affect the immune-phenotype and T-cell stimulatory activity of DCs. Our results suggest that systemic application of Fscn1 inhibitors for tumor therapy may also modulate antitumor immune responses. ABSTRACT: Background: Stimulated dendritic cells (DCs), which constitute the most potent population of antigen-presenting cells (APCs), express the actin-bundling protein Fascin-1 (Fscn1). In tumor cells, de novo expression of Fscn1 correlates with their invasive and metastatic properties. Therefore, Fscn1 inhibitors have been developed to serve as antitumor agents. In this study, we were interested in better understanding the impact of Fscn1 inhibitors on DCs. Methods: In parallel settings, murine spleen cells and bone-marrow-derived DCs (BMDCs) were stimulated with lipopolysaccharide in the presence of Fscn1 inhibitors (NP-G2-044 and BDP-13176). An analysis of surface expression of costimulatory and coinhibitory receptors, as well as cytokine production, was performed by flow cytometry. Cytoskeletal alterations were assessed by confocal microscopy. The effects on the interactions of BMDCs with antigen-specific T cells were monitored by time lapse microscopy. The T-cell stimulatory and polarizing capacity of BMDCs were measured in proliferation assays and cytokine studies. Results: Administration of Fscn1 inhibitors diminished Fscn1 expression and the formation of dendritic processes by stimulated BMDCs and elevated CD273 (PD-L2) expression. Fscn1 inhibition attenuated the interaction of DCs with antigen-specific T cells and concomitant T-cell proliferation. Conclusions: Systemic administration of Fscn1 inhibitors for tumor therapy may also modulate DC-induced antitumor immune responses. |
format | Online Article Text |
id | pubmed-9179534 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-91795342022-06-10 Inhibitors of the Actin-Bundling Protein Fascin-1 Developed for Tumor Therapy Attenuate the T-Cell Stimulatory Properties of Dendritic Cells Zeyn, Yanira Harms, Gregory Tubbe, Ingrid Montermann, Evelyn Röhrig, Nadine Hartmann, Maike Grabbe, Stephan Bros, Matthias Cancers (Basel) Article SIMPLE SUMMARY: Expression of the actin-bundling protein Fascin-1 (Fscn1) is largely restricted to neuronal cells and to activated dendritic cells (DCs). DCs are important inducers of (antitumor) immune responses. In tumor cells, de novo expression of Fscn-1 correlates with their invasive and metastatic activities. Pharmacological Fscn1 inhibitors, which are currently under clinical trials for tumor therapy, were demonstrated to counteract tumor metastasis. Within this study, we were interested in better understanding the effects of Fscn1 inhibitors on DCs and discovered that two distinct Fascin-1 inhibitors affect the immune-phenotype and T-cell stimulatory activity of DCs. Our results suggest that systemic application of Fscn1 inhibitors for tumor therapy may also modulate antitumor immune responses. ABSTRACT: Background: Stimulated dendritic cells (DCs), which constitute the most potent population of antigen-presenting cells (APCs), express the actin-bundling protein Fascin-1 (Fscn1). In tumor cells, de novo expression of Fscn1 correlates with their invasive and metastatic properties. Therefore, Fscn1 inhibitors have been developed to serve as antitumor agents. In this study, we were interested in better understanding the impact of Fscn1 inhibitors on DCs. Methods: In parallel settings, murine spleen cells and bone-marrow-derived DCs (BMDCs) were stimulated with lipopolysaccharide in the presence of Fscn1 inhibitors (NP-G2-044 and BDP-13176). An analysis of surface expression of costimulatory and coinhibitory receptors, as well as cytokine production, was performed by flow cytometry. Cytoskeletal alterations were assessed by confocal microscopy. The effects on the interactions of BMDCs with antigen-specific T cells were monitored by time lapse microscopy. The T-cell stimulatory and polarizing capacity of BMDCs were measured in proliferation assays and cytokine studies. Results: Administration of Fscn1 inhibitors diminished Fscn1 expression and the formation of dendritic processes by stimulated BMDCs and elevated CD273 (PD-L2) expression. Fscn1 inhibition attenuated the interaction of DCs with antigen-specific T cells and concomitant T-cell proliferation. Conclusions: Systemic administration of Fscn1 inhibitors for tumor therapy may also modulate DC-induced antitumor immune responses. MDPI 2022-05-31 /pmc/articles/PMC9179534/ /pubmed/35681718 http://dx.doi.org/10.3390/cancers14112738 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Zeyn, Yanira Harms, Gregory Tubbe, Ingrid Montermann, Evelyn Röhrig, Nadine Hartmann, Maike Grabbe, Stephan Bros, Matthias Inhibitors of the Actin-Bundling Protein Fascin-1 Developed for Tumor Therapy Attenuate the T-Cell Stimulatory Properties of Dendritic Cells |
title | Inhibitors of the Actin-Bundling Protein Fascin-1 Developed for Tumor Therapy Attenuate the T-Cell Stimulatory Properties of Dendritic Cells |
title_full | Inhibitors of the Actin-Bundling Protein Fascin-1 Developed for Tumor Therapy Attenuate the T-Cell Stimulatory Properties of Dendritic Cells |
title_fullStr | Inhibitors of the Actin-Bundling Protein Fascin-1 Developed for Tumor Therapy Attenuate the T-Cell Stimulatory Properties of Dendritic Cells |
title_full_unstemmed | Inhibitors of the Actin-Bundling Protein Fascin-1 Developed for Tumor Therapy Attenuate the T-Cell Stimulatory Properties of Dendritic Cells |
title_short | Inhibitors of the Actin-Bundling Protein Fascin-1 Developed for Tumor Therapy Attenuate the T-Cell Stimulatory Properties of Dendritic Cells |
title_sort | inhibitors of the actin-bundling protein fascin-1 developed for tumor therapy attenuate the t-cell stimulatory properties of dendritic cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9179534/ https://www.ncbi.nlm.nih.gov/pubmed/35681718 http://dx.doi.org/10.3390/cancers14112738 |
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