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Sorafenib Induces Pyroptosis in Macrophages and Triggers Natural Killer Cell–Mediated Cytotoxicity Against Hepatocellular Carcinoma
Author(s) -
Hage Carina,
Hoves Sabine,
Strauss Léanne,
Bissinger Stefan,
Prinz Ylva,
Pöschinger Thomas,
Kiessling Fabian,
Ries Carola H.
Publication year - 2019
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.30666
Subject(s) - sorafenib , pyroptosis , cytotoxic t cell , cancer research , immunotherapy , natural killer cell , immune system , innate immune system , hepatocellular carcinoma , medicine , immunology , programmed cell death , apoptosis , biology , in vitro , biochemistry
Antiangiogenic and cytotoxic effects are considered the principal mechanisms of action of sorafenib, a multitarget kinase inhibitor approved for the treatment of hepatocellular carcinoma (HCC). We report that sorafenib also acts through direct immune modulation, indispensable for its antitumor activity. In vivo cell depletion experiments in two orthotopic HCC mouse models as well as in vitro analysis identified macrophages (MΦ) as the key mediators of the antitumoral effect and demonstrate a strong interdependency of MΦ and natural killer (NK) cells for efficient tumor cell killing. Caspase 1 analysis in sorafenib‐treated MΦ revealed an induction of pyroptosis. As a result, cytotoxic NK cells become activated when cocultured with sorafenib‐treated MΦ, leading to tumor cell death. In addition, sorafenib was found to down‐regulate major histocompatibility complex class I expression of tumor cells, which may reduce the tumor responsiveness to immune checkpoint therapies and favor NK‐cell response. In vivo cytokine blocking revealed that sorafenib efficacy is abrogated after inhibition of interleukins 1B and 18. Conclusion : We report an immunomodulatory mechanism of sorafenib involving MΦ pyroptosis and unleashing of an NK‐cell response that sets it apart from other spectrum kinase inhibitors as a promising immunotherapy combination partner for the treatment of HCC.