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Dose-Dependent Sorafenib-Induced Immunosuppression Is Associated with Aberrant NFAT Activation and Expression of PD-1 in T Cells

The multikinase inhibitor sorafenib is the only standard first-line therapy for hepatocellular carcinoma (HCC). Here, we report the dose-dependent effects of sorafenib on the immune response, which is related to nuclear factor of activated T cells 1 (NFAT1) activity. In vitro and in vivo experiments...

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Autores principales: Iyer, Renuka V., Maguire, Orla, Kim, Minhyung, Curtin, Leslie I., Sexton, Sandra, Fisher, Daniel T., Schihl, Sarah A., Fetterly, Gerald, Menne, Stephan, Minderman, Hans
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562672/
https://www.ncbi.nlm.nih.gov/pubmed/31100868
http://dx.doi.org/10.3390/cancers11050681
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author Iyer, Renuka V.
Maguire, Orla
Kim, Minhyung
Curtin, Leslie I.
Sexton, Sandra
Fisher, Daniel T.
Schihl, Sarah A.
Fetterly, Gerald
Menne, Stephan
Minderman, Hans
author_facet Iyer, Renuka V.
Maguire, Orla
Kim, Minhyung
Curtin, Leslie I.
Sexton, Sandra
Fisher, Daniel T.
Schihl, Sarah A.
Fetterly, Gerald
Menne, Stephan
Minderman, Hans
author_sort Iyer, Renuka V.
collection PubMed
description The multikinase inhibitor sorafenib is the only standard first-line therapy for hepatocellular carcinoma (HCC). Here, we report the dose-dependent effects of sorafenib on the immune response, which is related to nuclear factor of activated T cells 1 (NFAT1) activity. In vitro and in vivo experiments were performed with low and high doses of sorafenib using human T cells and spontaneous developed woodchuck HCC models. In vitro studies demonstrated that following exposure to a high dose of sorafenib the baseline activity of NFAT1 in T cells was significantly increased. In a parallel event, high dose sorafenib resulted in a significant decrease in T cell proliferation and increased the proportion of PD-1 expressing CD8+ T cells with NFAT1 activation. In the in vivo model, smaller tumors were detected in the low-dose sorafenib treated group compared to the placebo and high-dose treated groups. The low-dose sorafenib group showed a significant tumor growth delay with significantly more CD3+ cells in tumor. This study demonstrates that sorafenib has immunomodulatory effects in a dose- and time-dependent manner. Higher dose of sorafenib treatment was associated with immunosuppressive action. This observed effect of sorafenib should be taken into consideration in the selection of optimum starting dose for future trials.
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spelling pubmed-65626722019-06-17 Dose-Dependent Sorafenib-Induced Immunosuppression Is Associated with Aberrant NFAT Activation and Expression of PD-1 in T Cells Iyer, Renuka V. Maguire, Orla Kim, Minhyung Curtin, Leslie I. Sexton, Sandra Fisher, Daniel T. Schihl, Sarah A. Fetterly, Gerald Menne, Stephan Minderman, Hans Cancers (Basel) Article The multikinase inhibitor sorafenib is the only standard first-line therapy for hepatocellular carcinoma (HCC). Here, we report the dose-dependent effects of sorafenib on the immune response, which is related to nuclear factor of activated T cells 1 (NFAT1) activity. In vitro and in vivo experiments were performed with low and high doses of sorafenib using human T cells and spontaneous developed woodchuck HCC models. In vitro studies demonstrated that following exposure to a high dose of sorafenib the baseline activity of NFAT1 in T cells was significantly increased. In a parallel event, high dose sorafenib resulted in a significant decrease in T cell proliferation and increased the proportion of PD-1 expressing CD8+ T cells with NFAT1 activation. In the in vivo model, smaller tumors were detected in the low-dose sorafenib treated group compared to the placebo and high-dose treated groups. The low-dose sorafenib group showed a significant tumor growth delay with significantly more CD3+ cells in tumor. This study demonstrates that sorafenib has immunomodulatory effects in a dose- and time-dependent manner. Higher dose of sorafenib treatment was associated with immunosuppressive action. This observed effect of sorafenib should be taken into consideration in the selection of optimum starting dose for future trials. MDPI 2019-05-16 /pmc/articles/PMC6562672/ /pubmed/31100868 http://dx.doi.org/10.3390/cancers11050681 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
Iyer, Renuka V.
Maguire, Orla
Kim, Minhyung
Curtin, Leslie I.
Sexton, Sandra
Fisher, Daniel T.
Schihl, Sarah A.
Fetterly, Gerald
Menne, Stephan
Minderman, Hans
Dose-Dependent Sorafenib-Induced Immunosuppression Is Associated with Aberrant NFAT Activation and Expression of PD-1 in T Cells
title Dose-Dependent Sorafenib-Induced Immunosuppression Is Associated with Aberrant NFAT Activation and Expression of PD-1 in T Cells
title_full Dose-Dependent Sorafenib-Induced Immunosuppression Is Associated with Aberrant NFAT Activation and Expression of PD-1 in T Cells
title_fullStr Dose-Dependent Sorafenib-Induced Immunosuppression Is Associated with Aberrant NFAT Activation and Expression of PD-1 in T Cells
title_full_unstemmed Dose-Dependent Sorafenib-Induced Immunosuppression Is Associated with Aberrant NFAT Activation and Expression of PD-1 in T Cells
title_short Dose-Dependent Sorafenib-Induced Immunosuppression Is Associated with Aberrant NFAT Activation and Expression of PD-1 in T Cells
title_sort dose-dependent sorafenib-induced immunosuppression is associated with aberrant nfat activation and expression of pd-1 in t cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562672/
https://www.ncbi.nlm.nih.gov/pubmed/31100868
http://dx.doi.org/10.3390/cancers11050681
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