Abstract
BackgroundTumor-associated macrophages (TAMs) are abundant in gliomas and immunosuppressive TAMs are a barrier to emerging immunotherapies. It is unknown to what extent macrophages derived from peripheral blood adopt the phenotype of brain-resident microglia in pre-treatment gliomas. The relative proportions of blood-derived macrophages and microglia have been poorly quantified in clinical samples due to a paucity of markers that distinguish these cell types in malignant tissue.ResultsWe perform single-cell RNA-sequencing of human gliomas and identify phenotypic differences in TAMs of distinct lineages. We isolate TAMs from patient biopsies and compare them with macrophages from non-malignant human tissue, glioma atlases, and murine glioma models. We present a novel signature that distinguishes TAMs by ontogeny in human gliomas. Blood-derived TAMs upregulate immunosuppressive cytokines and show an altered metabolism compared to microglial TAMs. They are also enriched in perivascular and necrotic regions. The gene signature of blood-derived TAMs, but not microglial TAMs, correlates with significantly inferior survival in low-grade glioma. Surprisingly, TAMs frequently co-express canonical pro-inflammatory (M1) and alternatively activated (M2) genes in individual cells.ConclusionsWe conclude that blood-derived TAMs significantly infiltrate pre-treatment gliomas, to a degree that varies by glioma subtype and tumor compartment. Blood-derived TAMs do not universally conform to the phenotype of microglia, but preferentially express immunosuppressive cytokines and show an altered metabolism. Our results argue against status quo therapeutic strategies that target TAMs indiscriminately and in favor of strategies that specifically target immunosuppressive blood-derived TAMs.
Highlights
Tumor-associated macrophages (TAMs) are abundant in gliomas and immunosuppressive Tumorassociated macrophage (TAM) are a barrier to emerging immunotherapies
We found that putative TAMs identified from the whole-tumor scRNA-seq clustered together with TAMs sequenced from the CD11b + suspensions and away from putative neoplastic cells from the whole-tumor scRNA-seq
In a principal component analysis (PCA) of the combined table, we found that Principal component 1 (PC1) stratified TAMs into two distinct platform-independent populations (Fig. 3a, Additional file 2: Figure S2a)
Summary
Tumor-associated macrophages (TAMs) are abundant in gliomas and immunosuppressive TAMs are a barrier to emerging immunotherapies. It is unknown to what extent macrophages derived from peripheral blood adopt the phenotype of brain-resident microglia in pre-treatment gliomas. The relative proportions of blood-derived macrophages and microglia have been poorly quantified in clinical samples due to a paucity of markers that distinguish these cell types in malignant tissue. The cellular heterogeneity of tumor-associated macrophages (TAMs) is a critical roadblock to the development of cancer immunotherapies. Evidence suggests that subpopulations of TAMs are resistant to CSF1R inhibition [3]. Another example is acquired resistance to the anti-angiogenesis therapy bevacizumab. Blood-derived TAMs preferentially contribute to therapy resistance, relative to brainresident microglia [4]. CSF1R blockade exemplifies the status quo, which seeks to target TAMs indiscriminately even though TAMs can play both tumor-supportive and anti-tumor roles
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