An iron-rich subset of macrophages promotes tumor growth through a Bach1-Ednrb axis
Ian W. Folkert, William A. Molina Arocho, Tsun Ki Jerrick To, Samir Devalaraja, Irene S. Molina, Jason Shoush, Hesham Mohei, Li Zhai, Md. Naushad Akhtar, Veena Kochat, Emre Arslan, Alexander J. Lazar, Khalida Wani, William P. Israel, Zhan Zhang, V Sai Chaluvadi, Robert J. Norgard, Ying Liu, Ashley M. Fuller, Mai T. Dang, Robert E. Roses, Giorgos C. Karakousis, John T. Miura, Douglas Fraker, T.S. Karin Eisinger‐Mathason, M. Celeste Simon, Kristy Weber, Kai Tan, Yi Fan, Kunal Rai, Malay Haldar
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.