富含铁的巨噬细胞亚群通过 Bach1-Ednrb 轴促进肿瘤生长。
An iron-rich subset of macrophages promotes tumor growth through a Bach1-Ednrb axis.
机构信息
Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA, USA.
Institute for Immunology, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA, USA.
出版信息
J Exp Med. 2024 Oct 7;221(10). doi: 10.1084/jem.20230420. Epub 2024 Sep 30.
We define a subset of macrophages in the tumor microenvironment characterized by high intracellular iron and enrichment of heme and iron metabolism genes. These iron-rich tumor-associated macrophages (iTAMs) supported angiogenesis and immunosuppression in the tumor microenvironment and were conserved between mice and humans. iTAMs comprise two additional subsets based on gene expression profile and location-perivascular (pviTAM) and stromal (stiTAM). We identified the endothelin receptor type B (Ednrb) as a specific marker of iTAMs and found myeloid-specific deletion of Ednrb to reduce tumor growth and vascular density. Further studies identified the transcription factor Bach1 as a repressor of the iTAM transcriptional program, including Ednrb expression. Heme is a known inhibitor of Bach1, and, correspondingly, heme exposure induced Ednrb and iTAM signature genes in macrophages. Thus, iTAMs are a distinct macrophage subset regulated by the transcription factor Bach1 and characterized by Ednrb-mediated immunosuppressive and angiogenic functions.
我们定义了肿瘤微环境中的一组巨噬细胞亚群,其特征是细胞内铁含量高,富含血红素和铁代谢基因。这些富含铁的肿瘤相关巨噬细胞(iTAMs)在肿瘤微环境中支持血管生成和免疫抑制,并且在小鼠和人类之间是保守的。iTAMs 根据基因表达谱和位置分为两个额外的亚群——血管周(pviTAM)和基质(stiTAM)。我们确定内皮素受体 B(Ednrb)是 iTAMs 的特异性标志物,并发现骨髓细胞特异性缺失 Ednrb 可减少肿瘤生长和血管密度。进一步的研究确定转录因子 Bach1 是 iTAM 转录程序的抑制剂,包括 Ednrb 的表达。血红素是 Bach1 的已知抑制剂,相应地,血红素暴露诱导巨噬细胞中 Ednrb 和 iTAM 特征基因的表达。因此,iTAMs 是受转录因子 Bach1 调节的一个独特的巨噬细胞亚群,其特征是 Ednrb 介导的免疫抑制和血管生成功能。