Controlling the Phenotype of Tumor-Infiltrating Macrophages via the PHD-HIF Axis Inhibits Tumor Growth in a Mouse Model
Controlling the Phenotype of Tumor-Infiltrating Macrophages via the PHD-HIF Axis Inhibits Tumor Growth in a Mouse Model
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DOI：
10.1016/j.isci.2019.08.033
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发表时间：
2019-08
期刊：
影响因子：
5.8
通讯作者：
S. Nishide;S. Matsunaga;M. Shiota;Takehiro Yamaguchi;S. Kitajima;Y. Maekawa;Norihiko Takeda;M. Tomura;J. Uchida;K. Miura;T. Nakatani;S. Tomita
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文献类型：
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作者：
S. Nishide;S. Matsunaga;M. Shiota;Takehiro Yamaguchi;S. Kitajima;Y. Maekawa;Norihiko Takeda;M. Tomura;J. Uchida;K. Miura;T. Nakatani;S. Tomita
肿瘤微环境（TME）使肿瘤浸润性巨噬细胞向肿瘤支持极化。巨噬细胞丰富的肿瘤是高度恶性的，并且是预后差和治疗抗性的原因。在这项研究中，我们表明脯氨酰羟化酶（PHD）抑制剂FG-4592（FG）抑制巨噬细胞丰富的肿瘤的肿瘤生长和小鼠存活。FG不仅使肿瘤血管正常化并改善肿瘤氧合，而且还直接影响巨噬细胞并通过PHD-缺氧诱导因子（HIF）轴激活吞噬作用。值得注意的是，FG可以促进肿瘤浸润性巨噬细胞的Ly 6Cl 0亚群的吞噬能力，导致肿瘤生长抑制。此外，Ly 6C巨噬细胞有助于血管正常化。使用恶性肿瘤小鼠模型，我们的特点是巨噬细胞的功能和子集。总之，我们的研究结果表明，PHD抑制剂可以促进巨噬细胞的抗肿瘤潜力，以改善癌症治疗。
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 Ly6Closubset of tumor-infiltrating macrophages, leading to tumor growth inhibition. Moreover, Ly6Cnegmacrophages 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.