Controlling the Phenotype of Tumor-Infiltrating Macrophages via the PHD-HIF Axis Inhibits Tumor Growth in a Mouse Model

• Main Authors: Shunji Nishide, Shinji Matsunaga, Masayuki Shiota, Takehiro Yamaguchi, Shojiro Kitajima, Yoichi Maekawa, Norihiko Takeda, Michio Tomura, Junji Uchida, Katsuyuki Miura, Tatsuya Nakatani, Shuhei Tomita
• Format: Article
• Language: English
• Published: Elsevier 2019-09-01
• Series: iScience
• Online Access: http://www.sciencedirect.com/science/article/pii/S2589004219303116

Summary: The tumor microenvironment (TME) polarizes tumor-infiltrating macrophages toward tumor support. Macrophage-abundant tumors are highly malignant and are the cause of poor prognosis and therapeutic resistance. In this study, we show that the prolyl hydroxylase (PHD) inhibitor FG-4592 (FG) inhibits tumor growth of macrophage-abundant tumors and prolongs mouse survival. FG not only normalizes tumor vessels and improves tumor oxygenation but also directly affects macrophages and activates phagocytosis through the PHD-hypoxia-inducible factor (HIF) axis. Remarkably, FG can promote phagocytic ability of the Ly6Clo subset of tumor-infiltrating macrophages, leading to tumor growth inhibition. Moreover, Ly6Cneg macrophages contributed to blood vessel normalization. Using a malignant tumor mouse model, we characterized macrophage function and subsets. Altogether, our findings suggest that the PHD inhibitor can promote the anti-tumor potential of macrophages to improve cancer therapy. : Microenvironment; Immune Response; Cancer Subject Areas: Microenvironment, Immune Response, Cancer