Single-cell characterization of macrophages in glioblastoma reveals MARCO as a mesenchymal pro-tumor marker

Andrew X Chen,Antonio Iavarone,Wenting Zhao,Pavan S Upadhyayula,Anna Lasorella,Athanassios Dovas,Peter A Sims,Hanna E Minns,Junfei Zhao,Jeffrey N Bruce,Jinzhou Yuan,Robyn D Gartrell,Raul Rabadan,Peter Canoll

doi:10.1186/s13073-021-00906-x

Abstract

BackgroundMacrophages are the most common infiltrating immune cells in gliomas and play a wide variety of pro-tumor and anti-tumor roles. However, the different subpopulations of macrophages and their effects on the tumor microenvironment remain poorly understood.MethodsWe combined new and previously published single-cell RNA-seq data from 98,015 single cells from a total of 66 gliomas to profile 19,331 individual macrophages.ResultsUnsupervised clustering revealed a pro-tumor subpopulation of bone marrow-derived macrophages characterized by the scavenger receptor MARCO, which is almost exclusively found in IDH1-wild-type glioblastomas. Previous studies have implicated MARCO as an unfavorable marker in melanoma and non-small cell lung cancer; here, we find that bulk MARCO expression is associated with worse prognosis and mesenchymal subtype. Furthermore, MARCO expression is significantly altered over the course of treatment with anti-PD1 checkpoint inhibitors in a response-dependent manner, which we validate with immunofluorescence imaging.ConclusionsThese findings illustrate a novel macrophage subpopulation that drives tumor progression in glioblastomas and suggest potential therapeutic targets to prevent their recruitment.

Highlights

Macrophages are the most common infiltrating immune cells in gliomas and play a wide variety of pro-tumor and anti-tumor roles
Looking at the expression of MARCO in all cell populations, we found that it is found in this subpopulation of macrophages (Additional file 3: Fig. S3A)
Absence of MARCO expression in Lower-grade glioma (LGG) and IDH1-mutant GBM We investigated whether this macrophage subpopulation could be observed in lower-grade gliomas (LGGs), which include grade II and III astrocytomas as well as oligodendrogliomas

Summary

Introduction

Macrophages are the most common infiltrating immune cells in gliomas and play a wide variety of pro-tumor and anti-tumor roles. Chen et al Genome Medicine (2021) 13:88 Targeting these TAMs (such as with CSF1R inhibitors) is an intriguing therapeutic option but requires a better understanding of markers specific to and necessary for TAM functioning [9,10,11]. Our classical knowledge of macrophage polarization (M1 vs M2) provides a simplified illustration of these different states [4]. This is clearly not the whole picture, given that M1 and M2 genes are often co-expressed in individual TAMs [12]. The specific markers and pathways involved in pro-tumor macrophages in GBM still remain elusive

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Discussion

Conclusion