Single-cell profiling of human gliomas reveals macrophage ontogeny as a basis for regional differences in macrophage activation in the tumor microenvironment

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-017-1362-4) contains supplementary material, which is available to authorized users.

Single-Cell Map of Diverse Immune Phenotypes in the Breast Tumor Microenvironment

“…All three of the TAM populations, particularly clusters 23 and 28, were among the monocytic clusters with the highest expression of the canonical M2 signature, but were likewise high in the M1 signature (Figure S7E). Quite strikingly, we found that M1 and M2 gene signatures positively correlated in the myeloid populations (Figure 7G), in line with recent findings in other tumor types (Muller et al, 2017). These findings support the idea that macrophage activation in the tumor microenvironment does not comport with the polarization model, either as discrete states or along a spectrum of alternative polarization trajectories.…”

Expression profiling of single cells and patient cohorts identifies multiple immunosuppressive pathways and an altered NK cell phenotype in glioblastoma

“…Muller et al . demonstrate that infiltrating macrophages rather than resident microglia encode immunosuppressive cytokines within the GBM microenvironment . Thus, immunosuppressive pathways operating in the GBM‐free brain are utilized and extended upon by infiltrating myeloid cells, contributing to the extensive immunosuppressive network.…”

“…The expression of genes such as HAVCR2 and its ligand LGALS9 and CD274, together with TGFB2 and IL-10, safeguard the normal brain against excessive inflammation [48]. Muller et al demonstrate that infiltrating macrophages rather than resident microglia encode immunosuppressive cytokines within the GBM microenvironment [49]. Thus, immunosuppressive pathways operating in the GBM-free brain are utilized and extended upon by infiltrating myeloid cells, contributing to the extensive immunosuppressive network.…”

Expression profiling of single cells and patient cohorts identifies multiple immunosuppressive pathways and an altered NK cell phenotype in glioblastoma

“…The expression of genes such as HAVCR2, its ligand LGALS9 and CD274, along with TGFB2 and IL10 safeguard the normal brain against excessive inflammation (43). Muller et al demonstrate that infiltrating macrophages rather than resident microglia encode immunosuppressive cytokines within the GBM microenvironment (44). Thus, immunosuppressive pathways operating in the GBM-free brain are utilised and extended upon by infiltrating myeloid cells, contributing to the extensive immunosuppressive network.…”