A Microglial Subset at the Tumor‐Stroma Border in High Grade Glioma

Abstract

Standard of care for Grade IV Glioblastoma (GB) currently results in a very short 14–16 month survival window for newly diagnosed patients. Even with maximal surgical resection, rates of recurrence, progression, and mortality are virtually absolute. The invasive nature of GB into the surrounding tissue is thought to be a major factor of disease progression/recurrence. Thus, there is great interest to characterize the GB tumor microenvironment (TME) to target non‐cancerous, stromal cells via immunotherapeutic avenues. The TME in CNS tumors such as GB is unique in that it contains an abundance of neural tissue and specialized glial cells, including the resident innate immune cells, microglia. In GB, glioma‐associated microglia and peripherally infiltrating monocytes/macrophages (GAM) accumulate within the neoplastic lesion where they facilitate tumor growth and drive immunosuppression. Previously, it has been difficult to accurately differentiate microglia versus macrophage roles in GB progression/recurrence. Additionally, the consequences of spatial organization of these cells have not been studied. Here we characterize the tumor‐stroma border and identify peripheral glioma associated microglia (PGAM) at the leading edge as a unique cellular subpopulation of bona fide GAM. Using data mining and analysis of several scRNAseq datasets derived from patients with varying glioma diagnoses, we show that PGAM exhibit a pro‐inflammatory and chemotactic phenotype. We cross‐validate these findings in a murine model of GB, and propose that PGAM may constitute a novel cellular target in the TME.