Tumor cell-imposed iron restriction drives immunosuppressive polarization of tumor-associated macrophages

作者：Jialei Sun, Ning‐Ping Zhang, Ru-Chen Xu, Guangcong Zhang, Zhiyong Liu, Weinire Abuduwaili, Fu Wang, Xiang‐Nan Yu, Xuan Shi, Guangqi Song, Hao Wu, Taotao Liu, Xizhong Shen, Bin Deng, Shu‐Qiang Weng, Ling Dong, Ji‐Min Zhu · 发表于：Journal of Translational Medicine · 年份：2021 · DOI：10.1186/s12967-021-03034-7 · 被引用次数：60 · 研究领域：Immune cells in cancer、Phagocytosis and Immune Regulation、Ferroptosis and cancer prognosis

BACKGROUND: Tumor-associated macrophages (TAM) are immunosuppressive cells that contribute to impaired anti-cancer immunity. Iron plays a critical role in regulating macrophage function. However, it is still elusive whether it can drive the functional polarization of macrophages in the context of cancer and how tumor cells affect the iron-handing properties of TAM. In this study, using hepatocellular carcinoma (HCC) as a study model, we aimed to explore the effect and mechanism of reduced ferrous iron in TAM. METHODS: TAM from HCC patients and mouse HCC tissues were collected to analyze the level of ferrous iron. Quantitative real-time PCR was used to assess M1 or M2 signature genes of macrophages treated with iron chelators. A co-culture system was established to explore the iron competition between macrophages and HCC cells. Flow cytometry analysis was performed to determine the holo-transferrin uptake of macrophages. HCC samples from The Cancer Genome Atlas (TCGA) were enrolled to evaluate the prognostic value of transferrin receptor (TFRC) and its relevance to tumor-infiltrating M2 macrophages. RESULTS: We revealed that ferrous iron in M2-like TAM is lower than that in M1-like TAM. In vitro analysis showed that loss of iron-induced immunosuppressive M2 polarization of mouse macrophages. Further experiments showed that TFRC, the primary receptor for transferrin-mediated iron uptake, was overexpressed on HCC cells but not TAM. Mechanistically, HCC cells competed with macrop...