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.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most prevalent type of cancer, and one of the leading causes of cancer-related death globally [1]
The dose-dependent effects of sorafenib exposure on the nuclear translocation of nuclear factor of activated T cells 1 (NFAT1) were studied in healthy human T cells
The data demonstrated that following exposure to high dose (10 μM) sorafenib in the absence of CD3/CD28 stimulation the baseline activity of NFAT1 in T cells was significantly increased
Summary
Hepatocellular carcinoma (HCC) is the fifth most prevalent type of cancer, and one of the leading causes of cancer-related death globally [1]. Sorafenib (Nexavar® , Bayer, Pittsburgh, PA, USA) is currently the only systemic agent approved for use in HCC. It is an orally administered multikinase inhibitor. It inhibits multiple cell surface tyrosine kinases, vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, platelet-derived growth factor-β, Fms-like tyrosine kinase-3, and downstream intracellular serine/threonine kinase in the mitogen-activated protein kinase (MAPK) cascade. These kinases are involved in tumor cell signaling, proliferation, angiogenesis, and apoptosis [6,7,8]. Chen and colleagues have reported that sorafenib relieves inhibition of effector
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