Abstract

BackgroundMyeloid involvement in High Grade Gliomas, such as Glioblastoma, has become apparent and detrimental to disease outcomes. There is great interest in characterizing the HGG tumor microenvironment to understand how neoplastic lesions are supported, and to devise novel therapeutic targets. The tumor microenvironment of the central nervous system is unique as it contains neural and specialized glial cells, including the resident myeloid cells, microglia. Glioma-associated microglia and peripherally infiltrating monocytes/macrophages (GAM) accumulate within the neoplastic lesion where they facilitate tumor growth and drive immunosuppression. A longstanding limitation has been the ability to accurately differentiate microglia and macrophage roles in pathology, and identify the consequences of the spatial organization of these cells. ResultsHere we characterize the tumor-stroma border and identify peripheral glioma-associated microglia (PGAM) at the tumor leading edge as a unique subpopulation of GAM. Using data mining and analyses of samples derived from both murine and human sources, we show that PGAM exhibit a pro-inflammatory and chemotactic phenotype that is associated with peripheral monocyte recruitment, poorly enhancing radiomic features, and decreased overall survival. ConclusionsPGAM act as a unique subset of GAM, at the tumor-stroma interface, corresponding to disease outcomes. We propose the application of a novel gene signature to identify these cells, and suggest that PGAM constitute a cellular target of the TME. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=126 SRC="FIGDIR/small/357459v1_ufig1.gif" ALT="Figure 1"> View larger version (76K): org.highwire.dtl.DTLVardef@6c08b6org.highwire.dtl.DTLVardef@b01421org.highwire.dtl.DTLVardef@1f99f9aorg.highwire.dtl.DTLVardef@15d5011_HPS_FORMAT_FIGEXP M_FIG C_FIG