Sorafenib Induces Pyroptosis in Macrophages and Triggers Natural Killer Cell–Mediated Cytotoxicity Against Hepatocellular Carcinoma

Abstract

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. (Hepatology 2019;70:1280-1297). L iver cancer is the second leading cause of cancer-related deaths worldwide.(1) Hepatocellular carcinoma (HCC) is the most common subtype of liver cancer, with increasing incidence and dismal prognosis. Hepatitis B and C viral infection, alcoholism, as well as nonalcoholic steatohepatitis are predominant risk factors for HCC development. (2) Sorafenib, a broad-spectrum kinase inhibitor, has been approved since 2007 for treating patients with unresectable HCC. (3) This adenosine triphosphate-competitive kinase inhibitor targets B-Raf, C-Raf, mitogen-activated protein (MAP) kinases, vascular endothelial growth factor (VEGF) receptor, and platelet-derived growth factor

Induction of Pyroptosis: A Promising Strategy for Cancer Treatment

“…In contrast to normal tissues, caspase-1 is low-expressed in hepatocellular carcinoma (HCC (73). The expression levels of caspase-1 and NLRP3 are lower in colorectal cancer (CRC) than adjacent tissues, indicating that pyroptosis associated proteins are negatively correlated with the tumorigenesis and development of CRC.…”

Sorafenib-loaded hydroxyethyl starch-TG100-115 micelles for the treatment of liver cancer based on synergistic treatment

“…For sorafenib, it has dual anti-tumor effect according to the reports (Dong et al., 2019). It can directly inhibit the proliferation of tumor cells by blocking the RAF/MEK/ERK-mediated cell signaling pathway, and can also inhibit tumor growth by inhibiting the formation of new blood vessels by acting on VEGFR (Hage et al., 2019). However, although sorafenib can inhibit the growth of tumors in situ , but it can mobilize a large number of macrophages into the blood and promotes the activation of macrophages to M2 type.…”

Characterizing responsive and refractory orthotopic mouse models of hepatocellular carcinoma in cancer immunotherapy

“…Cancer vaccines, CAR T cells and adoptive transfer of immune effector cells are promising approaches to provide tumor specific immune cells and mediate tumor regression [49]. Another effective option to treat HCC in immune-tolerant models is the TKI sorafenib, which has been shown to inhibit tumor growth and prolong survival of iAST mice [32, 50].…”