Attenuation of CD47-SIRPα Signal in Cholangiocarcinoma Potentiates Tumor-Associated Macrophage-Mediated Phagocytosis and Suppresses Intrahepatic Metastasis

Kulthida Vaeteewoottacharn; Ryusho Kariya; Phattarin Pothipan; Sawako Fujikawa; Chawalit Pairojkul; Sakda Waraasawapati; Kazuhiko Kuwahara; Chaisiri Wongkham; Sopit Wongkham; Seiji Okada

doi:10.1016/j.tranon.2018.10.007

Attenuation of CD47-SIRPα Signal in Cholangiocarcinoma Potentiates Tumor-Associated Macrophage-Mediated Phagocytosis and Suppresses Intrahepatic Metastasis

Transl Oncol. 2019 Feb;12(2):217-225. doi: 10.1016/j.tranon.2018.10.007. Epub 2018 Nov 9.

Affiliations

¹ Division of Hematopoiesis, Center for AIDS research and Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand.
² Division of Hematopoiesis, Center for AIDS research and Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
³ Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand.
⁴ Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand; Department of Pathology Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
⁵ Department of Diagnostic Pathology, Fujita Health University School of Medicine, Toyoake, Japan.
⁶ Division of Hematopoiesis, Center for AIDS research and Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. Electronic address: okadas@kumamoto-u.ac.jp.

Abstract

The involvement of chronic inflammation in cholangiocarcinoma (CCA) progression is well established. Cluster of differentiation 47 (CD47) is mutually expressed in various cancers and serves as a protective signal for phagocytic elimination. CD47 signaling blockage is a recent treatment strategy; however, little is known regarding CD47 in CCA. Therefore, the potential use of CD47 targeting in CCA was focused. CD47 was highly expressed in CCA compared to hepatocellular carcinoma (HCC). Disturbance of CD47-signal regulatory protein-α (SIRPα) interaction by blocking antibodies promoted the macrophage phagocytosis. The therapeutic potential of anti-CD47 therapy was demonstrated in liver metastatic model; alleviation of cancer colonization together with dense macrophage infiltrations was observed. The usefulness of anti-CD47 was emphasized by its universal facilitating macrophage activities. Moreover, increased production of inflammatory cytokines, such as IL-6 and IL-10, in macrophage exposed to CCA-conditioned media suggested that CCA alters macrophages toward cancer promotion. Taken together, interfering of CD47-SIRPα interaction promotes macrophage phagocytosis in all macrophage subtypes and consequently suppresses CCA growth and metastasis. The unique overexpression of CD47 in CCA but not HCC offers an exceptional opportunity for a targeted therapy. CD47 is therefore a novel target for CCA treatment.