转铁蛋白受体
癌症研究
巨噬细胞极化
铁转运蛋白
转铁蛋白
肝细胞癌
流式细胞术
生物
医学
巨噬细胞
免疫学
体外
内科学
海西定
炎症
生物化学
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,Shuqiang Weng,Ling Dong,Ji‐Min Zhu
标识
DOI:10.1186/s12967-021-03034-7
摘要
Abstract 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 macrophages for iron to upregulate the expression of M2-related genes via induction of HIF-1α, thus contributing to M2-like TAM polarization. We further clarified the oncogenic role of TFRC in HCC patients by TCGA. TFRC is significantly increased in varieties of malignancies, including HCC, and HCC patients with high TFRC levels have considerably shortened overall survival. Also, TFRC is shown to be positively related to tumor-infiltrating M2 macrophages. Conclusions Collectively, we identified iron starvation through TFRC-mediated iron competition drives functional immunosuppressive polarization of TAM, providing new insight into the interconnection between iron metabolism and tumor immunity.
科研通智能强力驱动
Strongly Powered by AbleSci AI