title: Immune modulation of effector CD4+ and regulatory T cell function by sorafenib in patients with hepatocellular carcinoma.
abstract: 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.
authors.affiliation: Department of Medicine, Section of Hepatobiliary Diseases, University of Florida, 1600 SW Archer Rd., P.O. Box 100214, Gainesville, FL 32610-0214, USA. rcabrera@ufl.edu
authors.forename: Roniel
authors.initials: R
authors.lastname: Cabrera
authors.forename: Miguel
authors.initials: M
authors.lastname: Ararat
authors.forename: Yiling
authors.initials: Y
authors.lastname: Xu
authors.forename: Todd
authors.initials: T
authors.lastname: Brusko
authors.forename: Clive
authors.initials: C
authors.lastname: Wasserfall
authors.forename: Mark A
authors.initials: MA
authors.lastname: Atkinson
authors.forename: Lung Ji
authors.initials: LJ
authors.lastname: Chang
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.forename: David R
authors.initials: DR
authors.lastname: Nelson
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000276:immunology*; D016022:Case-Control Studies; D018920:Coculture Techniques; D016207:Cytokines / Q000097:blood / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis / Q000276:immunology; D008113:Liver Neoplasms / Q000097:blood / Q000276:immunology*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D000077157:Sorafenib; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology*
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib