Faculty, Staff and Student Publications
Publication Date
10-7-2024
Journal
Journal of Experimental Medicine
Abstract
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.
Keywords
Basic-Leucine Zipper Transcription Factors, Animals, Iron, Mice, Humans, Tumor Microenvironment, Heme, Tumor-Associated Macrophages, Neovascularization, Pathologic, Macrophages, Mice, Inbred C57BL, Gene Expression Regulation, Neoplastic, Cell Line, Tumor
DOI
10.1084/jem.20230420
PMID
39347789
PMCID
PMC11457473
PubMedCentral® Posted Date
9-30-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons