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Inhibition of Heme Oxygenase-1 Activity Enhances Wilms Tumor-1-Specific T-Cell Responses in Cancer Immunotherapy

Wilms tumor protein-1 (WT1) is an attractive target for adoptive T-cell therapy due to its expression in solid tumors and hematologic malignancies. However, T cells recognizing WT1 occur in low frequencies in the peripheral blood of healthy donors, limiting potential therapeutic possibilities. Tin m...

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Autores principales: Schillingmann, Damaris A., Riese, Sebastian B., Vijayan, Vijith, Tischer-Zimmermann, Sabine, Schmetzer, Helga, Maecker-Kolhoff, Britta, Blasczyk, Rainer, Immenschuh, Stephan, Eiz-Vesper, Britta
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6387130/
https://www.ncbi.nlm.nih.gov/pubmed/30678050
http://dx.doi.org/10.3390/ijms20030482
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author Schillingmann, Damaris A.
Riese, Sebastian B.
Vijayan, Vijith
Tischer-Zimmermann, Sabine
Schmetzer, Helga
Maecker-Kolhoff, Britta
Blasczyk, Rainer
Immenschuh, Stephan
Eiz-Vesper, Britta
author_facet Schillingmann, Damaris A.
Riese, Sebastian B.
Vijayan, Vijith
Tischer-Zimmermann, Sabine
Schmetzer, Helga
Maecker-Kolhoff, Britta
Blasczyk, Rainer
Immenschuh, Stephan
Eiz-Vesper, Britta
author_sort Schillingmann, Damaris A.
collection PubMed
description Wilms tumor protein-1 (WT1) is an attractive target for adoptive T-cell therapy due to its expression in solid tumors and hematologic malignancies. However, T cells recognizing WT1 occur in low frequencies in the peripheral blood of healthy donors, limiting potential therapeutic possibilities. Tin mesoporphyrin (SnMP) is known to inhibit heme oxygenase-1 (HO-1), which has been shown to boost the activation and proliferation of human virus-specific T cells. We analyzed the influence of this effect on the generation of WT1-specific T cells and developed strategies for generating quantities of these cells from healthy donors, sufficient for adoptive T-cell therapies. HO-1 inhibition with SnMP increased WT1-specific T-cell frequencies in 13 (26%) of 50 healthy donors. To assess clinical applicability, we measured the enrichment efficiency of SnMP-treated WT1-specific T cells in response to a WT1-specific peptide pool and a HLA-A*02:01-restricted WT1 peptide by cytokine secretion assay. SnMP treatment resulted in a 28-fold higher enrichment efficacy with equal functionality. In conclusion, pharmacological inhibition of HO-1 activity with SnMP results in more efficient generation of functionally active WT1-specific T cells. This study demonstrates the therapeutic potentials of inhibiting HO-1 with SnMP to enhance antigen-specific T-cell responses in the treatment of cancer patients with WT1-positive disease.
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spelling pubmed-63871302019-02-27 Inhibition of Heme Oxygenase-1 Activity Enhances Wilms Tumor-1-Specific T-Cell Responses in Cancer Immunotherapy Schillingmann, Damaris A. Riese, Sebastian B. Vijayan, Vijith Tischer-Zimmermann, Sabine Schmetzer, Helga Maecker-Kolhoff, Britta Blasczyk, Rainer Immenschuh, Stephan Eiz-Vesper, Britta Int J Mol Sci Article Wilms tumor protein-1 (WT1) is an attractive target for adoptive T-cell therapy due to its expression in solid tumors and hematologic malignancies. However, T cells recognizing WT1 occur in low frequencies in the peripheral blood of healthy donors, limiting potential therapeutic possibilities. Tin mesoporphyrin (SnMP) is known to inhibit heme oxygenase-1 (HO-1), which has been shown to boost the activation and proliferation of human virus-specific T cells. We analyzed the influence of this effect on the generation of WT1-specific T cells and developed strategies for generating quantities of these cells from healthy donors, sufficient for adoptive T-cell therapies. HO-1 inhibition with SnMP increased WT1-specific T-cell frequencies in 13 (26%) of 50 healthy donors. To assess clinical applicability, we measured the enrichment efficiency of SnMP-treated WT1-specific T cells in response to a WT1-specific peptide pool and a HLA-A*02:01-restricted WT1 peptide by cytokine secretion assay. SnMP treatment resulted in a 28-fold higher enrichment efficacy with equal functionality. In conclusion, pharmacological inhibition of HO-1 activity with SnMP results in more efficient generation of functionally active WT1-specific T cells. This study demonstrates the therapeutic potentials of inhibiting HO-1 with SnMP to enhance antigen-specific T-cell responses in the treatment of cancer patients with WT1-positive disease. MDPI 2019-01-23 /pmc/articles/PMC6387130/ /pubmed/30678050 http://dx.doi.org/10.3390/ijms20030482 Text en © 2019 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Schillingmann, Damaris A.
Riese, Sebastian B.
Vijayan, Vijith
Tischer-Zimmermann, Sabine
Schmetzer, Helga
Maecker-Kolhoff, Britta
Blasczyk, Rainer
Immenschuh, Stephan
Eiz-Vesper, Britta
Inhibition of Heme Oxygenase-1 Activity Enhances Wilms Tumor-1-Specific T-Cell Responses in Cancer Immunotherapy
title Inhibition of Heme Oxygenase-1 Activity Enhances Wilms Tumor-1-Specific T-Cell Responses in Cancer Immunotherapy
title_full Inhibition of Heme Oxygenase-1 Activity Enhances Wilms Tumor-1-Specific T-Cell Responses in Cancer Immunotherapy
title_fullStr Inhibition of Heme Oxygenase-1 Activity Enhances Wilms Tumor-1-Specific T-Cell Responses in Cancer Immunotherapy
title_full_unstemmed Inhibition of Heme Oxygenase-1 Activity Enhances Wilms Tumor-1-Specific T-Cell Responses in Cancer Immunotherapy
title_short Inhibition of Heme Oxygenase-1 Activity Enhances Wilms Tumor-1-Specific T-Cell Responses in Cancer Immunotherapy
title_sort inhibition of heme oxygenase-1 activity enhances wilms tumor-1-specific t-cell responses in cancer immunotherapy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6387130/
https://www.ncbi.nlm.nih.gov/pubmed/30678050
http://dx.doi.org/10.3390/ijms20030482
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