Sorafenib perpetuates cellular anticancer effector functions by modulating the crosstalk between macrophages and natural killer cells

• DOI: 10.1002/hep.26328
• Publication Date: 2013-02-19T19:57:47Z
• Authors: Martin Franz Sprinzl; Florian Reisinger; Andreas Puschnik; Marc Ringelhan; Kerstin Ackermann; Daniel Hartmann; Matthias Schiemann; Arndt Weinmann; Peter Robert Galle; Marcus Schuchmann; Helmut Friess; Gerd Otto; Mathias Heikenwalder; Ulrike Protzer
• Keywords: Niacinamide; 0301 basic medicine; Carcinoma, Hepatocellular; Macrophages; Phenylurea Compounds; Liver Neoplasms; Drug Evaluation, Preclinical; NF-kappa B; Antineoplastic Agents; Apoptosis; Macrophage Activation; Sorafenib; 3. Good health; Killer Cells, Natural; Mice, Inbred C57BL; Mice; 03 medical and health sciences; liver cancer; therapy; microenvironment; immunology; HCC; Animals; Cytokines; Humans

Alternatively polarized macrophages (Mϕ) shape the microenvironment of hepatocellular carcinoma (HCC) and temper anticancer immune responses. We investigated if sorafenib alters HCC by restoring classical macrophage polarization triggering tumor-directed natural killer (NK) cell In vivo experiments were conducted with (25 mg/kg)-treated C57BL/6 wildtype as well hepatitis B virus (HBV) lymphotoxin transgenic mice without HCC. Monocyte-derived Mϕ or tumor-associated (TAM) isolated from tissue treated (0.07-5.0 μg/mL) cocultured autologous NK cells. activation was analyzed flow cytometry killing assays, respectively. Cytokine growth factor release measured enzyme-linked immunosorbent assay. Short-term administration triggered hepatic cells in tumor-bearing mice. vitro, sensitized to lipopolysaccharide, reverted alternative enhanced IL12 secretion (P = 0.0133). activated sorafenib-treated showed increased degranulation (15.3 ± 0.2% versus 32.0 0.9%, P < 0.0001) interferon-gamma (IFN-γ) (2.1 8.0 0.2%, upon target contact. Sorafenib-triggered verified coculture using TAM. Sorafenib-treated cytolytic function against K562, Raji, HepG2 a dose-dependent manner. Neutralization interleukin (IL)12 IL18 inhibition nuclear kappa (NF-κB) pathway reversed Mϕ/NK cocultures. Conclusion: Sorafenib triggers proinflammatory activity TAM subsequently induces antitumor responses cytokine- NF-κB-dependent fashion. This observation is relevant for therapy, compound clinical use that reverts (HEPATOLOGY 2013;57:2358–2368)