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

1
Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
2
Flow and Image Cytometry Shared Resource, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
3
Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
4
Laboratory Animal Shared Resources, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
5
Bioanalytics, Metabolomics, and Pharmacokinetics Shared Resource, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
6
Department of Microbiology & Immunology, Georgetown University, Washington, DC 20057, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2019, 11(5), 681; https://doi.org/10.3390/cancers11050681
Received: 19 April 2019 / Revised: 14 May 2019 / Accepted: 14 May 2019 / Published: 16 May 2019
(This article belongs to the Special Issue Hepatocellular Cancer Treatment)
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Abstract

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. View Full-Text
Keywords: sorafenib; hepatocellular carcinoma; NFAT1; immunosuppression sorafenib; hepatocellular carcinoma; NFAT1; immunosuppression
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Iyer, R.V.; Maguire, O.; Kim, M.; Curtin, L.I.; Sexton, S.; Fisher, D.T.; Schihl, S.A.; Fetterly, G.; Menne, S.; Minderman, H. Dose-Dependent Sorafenib-Induced Immunosuppression Is Associated with Aberrant NFAT Activation and Expression of PD-1 in T Cells. Cancers 2019, 11, 681.

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