Z Gastroenterol 2011; 49 - P2_84
DOI: 10.1055/s-0030-1269601

Multi kinase inhibitor Sorafenib modulates cytokine secretion by HCC and liver tissue

MF Sprinzl 1, M Heise 2, A Weinmann 3, P Büchler 4, PR Galle 3, H Friess 4, G Otto 2, M Schuchmann 3, U Protzer 5
  • 1Institut für Virologie, Technische Universität München, München
  • 2Abteilung für Transplantationschirurgie Johannes Gutenberg-Universität Mainz, Mainz
  • 3I. Medizinische Klinik, Universität Mainz, Mainz
  • 4Chirurgische Klinik und Poliklinik, Klinikum rechts der Isar, München
  • 5Institut für Virologie, Technische Universität München / Helmholtz Zentrum München, München

Background: Local treatment of HCC induces inflammatory reactions and tumor specific immune responses, which may contribute to a favorable clinical outcome. Whether this holds true for systemic treatment with kinase inhibitors has not been studied. Hence, we have investigated cytokine profiles of liver and HCC tissue in presence of Sorafenib to analyse its immune modulatory capacity.

Methods: Liver and tumor specimens were obtained from patients undergoing liver resection for treatment of HCC without prior local or systemic therapy. HCC developed in context of liver cirrhosis due to viral hepatitis, alcoholic or metabolic liver disease. HCC and liver tissues were cultured for 10 days. Lymphocyte stimulating cytokines (IL2, IL7, IL15) and Sorafenib (5µg/ml) were added and IFN-y and IL10 was detected in the culture supernatant via ELISA.

Results: Liver-associated lymphocytes showed a higher spontaneous IFN-y secretion than HCC associated ones. During cytokine stimulation we observed a 3.3 fold induction of IFN-y secretion in liver tissue compared to a 1.79 fold induction in HCC tissue, respectively. Sorafenib reduced IFN-y secretion in tumor and liver tissue to background levels during a 3 day induction period. In contrast, IL10 secretion was neither altered by cytokine stimulation nor by Sorafenib. Nevertheless, absolute IL10 secretion remained higher in HCC tissue compared to liver tissue.

Conclusion: Decreased IFN-y secretion by HCC tissue lymphocytes indicates an impaired cellular immune response in HCC, which could be caused by a mitigating tumor environment mirrored by increased IL10 production. In this context, Sorafenib inhibited pro-inflammatory responses but did not affect IL10 secretion, indicating an overall immunmodulatory effect. To confirm these findings and identify mechanisms of Sorafenib induced immune modulation, studies with Sorafenib pretreated HCC patients including the characterization of immune cell subsets are ongoing.

Sorafenib - hepatocellular carcinoma - inflammation - kinase inhibitor