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

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.

Research trends in pharmacological modulation of tumor‐associated macrophages

“…A similar strategy targeting macrophages is also developing by blocking CD47 from binding its receptor signal regulatory protein‐α (SIRPα) on macrophage surface 413 . It has been reported that interfering of CD47‐SIRPα interaction by blocking antibodies could promote the phagocytosis of TAMs and consequently suppresses cholangiocarcinoma growth and metastasis 414 . Nowadays, a number of CD47‐SIRPα axis blockers, such as Hu5F9‐G4, CC‐90002, SRF231, ALX148, and IBI188, are under clinical trials 413 …”

Establishment of Highly Transplantable Cholangiocarcinoma Cell Lines from a Patient-Derived Xenograft Mouse Model

“…One to two million cells of each cell line were transplanted subcutaneously into both flanks of Balb/c RJ mice. For intrasplenic transplantation, 5 × 10 4 cells were injected intrasplenically as previously described [38]. Tissues, spleen, and liver were removed at 1 month after transplantation.…”

Tumor-associated macrophages in cholangiocarcinoma: complex interplay and potential therapeutic target

“…CCA cells express higher CD47 than HCC and serve as a "don't eat me signal", thus deceiving macrophages by binding to macrophages SIRPa. The blockage of CD47-SIRPa interactions by anti-CD47 results in increased macrophage infiltration and potentiated macrophage phagocytosis, leading to decreased cancer colonization in mice models [88]. Besides, macrophages have complex regulation effects on other immune cells of the TME.…”