Hepatocellular carcinoma (HCC) is a difficult to treat cancer characterized by poor tumor immunity with only one approved systemic drug, sorafenib. If novel combination treatments are to be developed with immunological agents, the effects of sorafenib on tumor immunity are important to understand. In this study, we investigate the impact of sorafenib on the CD4+CD25− effector T cells (Teff) and CD4+CD25+ regulatory T cells (Tregs) from patients with HCC. We isolated Teff and Treg from peripheral mononuclear cells of HCC patients to determine immune reactivity by thymidine incorporation, ELISA and flow cytometry. Teff cultured alone or with Treg were supplemented with different concentrations of sorafenib. The effects of sorafenib on Teff responses were dose-dependent. Pharmacologic doses of sorafenib decreased Teff activation by down regulating CD25 surface expression. In contrast, sub-pharmacologic concentrations of sorafenib resulted in Teff activation. These low doses of sorafenib in the Teff cultures led to a significant increase in Teff proliferation, IL2 secretion and up-regulation of CD25 expression on the cell surface. In addition, low doses of sorafenib in the suppression Teff/Treg cocultures restored Teff responses by eliminating Treg suppression. The loss of Treg suppressive function correlated with an increase in IL2 and IL6 secretion. Our findings show that sub-pharmacologic doses of sorafenib impact subsets of T cells differently, selectively increasing Teff activation while blocking Treg function. In conclusion, this study describes novel immune activating properties of low doses of sorafenib by promoting immune responsiveness in patients with HCC.
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The authors want to thank Neal Benson and Lynn Combee for expert technical assistance with the flow cytometer experiments. Research support for this study provided in part by National Institutes of Health/National Center for Research Resources Award UL1 RR029890 and National Institutes of Health/National Cancer Institute award K24CA139570.
Conflict of interest
Dr. Cabrera is a speaker, consultant, and has research grants from Bayer. Dr. Nelson is a consultant and has research grants from Bayer and Human Genome Science.
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Supplemental Figure 1 Low Doses of sorafenib does not impact cell function in controls. CD4+ T effector cells from normal healthy controls (NHC) and patients with well compensated cirrhosis but no cancer (DC) (n=6) were stimulated with PHA without sorafenib and with low doses of sorafenib (0.1uM and 1uM). No significant differences were observed in the normal healthy controls and disease controls when their PBMCs were stimulated with and without sorafenib. Supplementary material 1 (JPEG 158 kb)
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Cabrera, R., Ararat, M., Xu, Y. et al. Immune modulation of effector CD4+ and regulatory T cell function by sorafenib in patients with hepatocellular carcinoma. Cancer Immunol Immunother 62, 737–746 (2013). https://doi.org/10.1007/s00262-012-1380-8
- T cell
- Regulatory T cells
- Hepatocellular carcinoma