Macrophage Ontogeny Underlies Differences in Tumor-Specific Education in Brain Malignancies

Extensive transcriptional and ontogenetic diversity exists among normal tissue-resident macrophages, with unique transcriptional profiles endowing the cells with tissue-specific functions. However, it is unknown whether the origins of different macrophage populations affect their roles in malignancy. Given potential artifacts associated with irradiation-based lineage tracing, it remains unclear if bone-marrow-derived macrophages (BMDMs) are present in tumors of the brain, a tissue with no homeostatic involvement of BMDMs. Here, we employed multiple models of murine brain malignancy and genetic lineage tracing to demonstrate that BMDMs are abundant in primary and metastatic brain tumors. Our data indicate that distinct transcriptional networks in brain-resident microglia and recruited BMDMs are associated with tumor-mediated education yet are also influenced by chromatin landscapes established before tumor initiation. Furthermore, we demonstrate that microglia specifically repress Itga4 (CD49D), enabling its utility as a discriminatory marker between microglia and BMDMs in primary and metastatic disease in mouse and human. [Display omitted] •Peripherally derived macrophages (BMDMs) and microglia (MG) infiltrate brain tumors•BMDMs and MG possess distinct transcriptional profiles and activation states in cancer•Chromatin landscapes are distinct between BMDMs and MG•CD49D is absent on MG and distinguishes them from BMDMs in mouse and human tumors Bowman et al. use genetic lineage tracing models to interrogate the ontogeny of tumor-associated macrophages in brain malignancy. These studies show that bone-marrow-derived macrophages (BMDMs) and tissue-resident microglia (MG) are present in glioma and brain metastases, possessing distinct transcriptional and chromatin states, and identify markers distinguishing these cell populations.