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

• Published in: iScience Vol. 19; pp. 940 - 954
• Main Authors: Nishide, Shunji, Matsunaga, Shinji, Shiota, Masayuki, Yamaguchi, Takehiro, Kitajima, Shojiro, Maekawa, Yoichi, Takeda, Norihiko, Tomura, Michio, Uchida, Junji, Miura, Katsuyuki, Nakatani, Tatsuya, Tomita, Shuhei
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.09.2019; Elsevier
• Subjects: Cancer; Immune Response; Microenvironment; Immune Response; Microenvironment; Cancer
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2019.08.033

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. [Display omitted] •PHD inhibitor treatment inhibits tumor growth and prolongs survival time of mice•Regulating the PHD-HIF pathway can alter the tumor-infiltrating macrophage phenotype•PHD inhibitor activates the tumor phagocytic ability of Ly6Clo macrophages Microenvironment; Immune Response; Cancer