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

TLDR

Transcriptional and ontogenetic diversity among tissue‑resident macrophages is known, but it remains unclear whether macrophage origins influence their roles in brain malignancies or whether bone‑marrow‑derived macrophages infiltrate brain tumors, especially given potential artifacts of irradiation‑based lineage tracing. Using murine brain tumor models and genetic lineage tracing, the study shows that bone‑marrow‑derived macrophages are abundant in primary and metastatic brain tumors, that microglia and recruited macrophages exhibit distinct transcriptional networks shaped by pre‑tumor chromatin landscapes, and that microglia uniquely repress Itga4, allowing it to serve as a marker to distinguish them from macrophages in mouse and human tumors.

Abstract

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.