Short-term administration of sorafenib triggered activation of hepatic NK cells in wildtype and tumor-bearing mice. In vitro, sorafenib sensitized Mϕ to lipopolysaccharide,
reverted alternative Mϕ polarization and enhanced IL12 secretion Selleck Inhibitor Library (P = 0.0133). NK cells activated by sorafenib-treated Mϕ showed increased degranulation (15.3 ± 0.2% versus 32.0 ± 0.9%, P < 0.0001) and interferon-gamma (IFN-γ) secretion (2.1 ± 0.2% versus 8.0 ± 0.2%, P < 0.0001) upon target cell contact. Sorafenib-triggered NK cell activation was verified by coculture experiments using TAM. Sorafenib-treated Mϕ increased cytolytic NK cell function against K562, Raji, and HepG2 target cells in a dose-dependent manner. Neutralization of interleukin (IL)12 or IL18 as well as inhibition of the nuclear factor kappa B (NF-κB) pathway reversed NK cell activation in Mϕ/NK cocultures. Conclusion: Sorafenib triggers proinflammatory activity of TAM and subsequently induces antitumor NK cell responses in a cytokine- and NF-κB-dependent fashion. This observation is relevant for HCC therapy, as sorafenib is a compound in clinical use that reverts alternative polarization of TAM in HCC. (HEPATOLOGY 2013;57:2358–2368) Tumor-associated macrophages (TAM) located in the hepatocellular carcinoma (HCC) environment increase HCC recurrence after resection and reduce patient survival.1,
2 TAM thereby fosters tumor cell proliferation and tumor spread.3 Natural killer (NK) cell numbers and activity, on the other hand, are associated with lower HCC stages and improved selleck chemicals llc patient survival.4, 5 An outstanding feature of TAM is their cytokine-dependent inhibition of lymphocyte and NK cell functions.6 TAM also promote T-cell exhaustion7 and are associated with the intratumoral accumulation of regulatory cells contributing to immune tolerance.2 TAM themselves represent alternatively polarized macrophages (Mϕ), which are opposed by proinflammatory Mϕ populations.3 Mϕ plasticity therefore
balances tumor protection and immunogenic tumor rejection. Hence, interference with Mϕ polarization leading to an anticancer immune response represents a potential approach for therapy. Tyrosine kinase inhibitors are promising candidates for TAM-directed therapy, as Mϕ polarization is regulated by tyrosine kinases.3, 6 Sorafenib, a multi-tyrosine kinase inhibitor, Metalloexopeptidase has become a standard palliative treatment for HCC.8 Sorafenib blocks different tyrosine kinases, such as rat sarcoma (RAS), rat fibrosarcoma (RAF), and extracellular-regulated protein kinase (ERK), thereby inhibiting proliferation and survival of tumor cells. In combination with antiangiogenic effects, this eventually results in HCC regression.9 Previous reports also indicate that sorafenib subverts immune responses by mitigating mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) signaling.10, 11 In addition, inhibition of MAPKp38 by sorafenib may affect Mϕ polarization and innate immune surveillance.