Brain cancers carry bleak prognoses, with therapeutic advances helping only a minority of patients over the past decade. The brain tumour microenvironment (TME) is highly immunosuppressive and differs from that of other malignancies as a result of the glial, neural and immune cell populations that constitute it. Until recently, the study of the brain TME was limited by the lack of methods to de-convolute this complex system at the single-cell level. However, novel technical approaches have begun to reveal the immunosuppressive and tumour-promoting properties of distinct glial and myeloid cell populations in the TME, identifying new therapeutic opportunities. Here, we discuss the immune modulatory functions of microglia, monocyte-derived macrophages and astrocytes in brain metastases and glioma, highlighting their disease-associated heterogeneity and drawing from the insights gained by studying these malignancies and other neurological disorders. Lastly, we consider potential approaches for the therapeutic modulation of the brain TME.
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This work was supported by grants NS102807, ES02530, ES029136, AI126880 and AI149699 from the NIH; RG4111A1 and JF2161-A-5 from the NMSS, PA-1604-08459 from the International Progressive MS Alliance and the Jennifer Oppenheimer Cancer Research Initiative to F.J.Q. B.M.A. was supported by grant K12CA090354 from NIH. C.F.A. was supported by a scholarship from the German Academic Exchange Service (DAAD). M.A.W. was supported by NIH (1K99NS114111, F32NS101790), a training grant from the NIH and Dana-Farber Cancer Institute (T32CA207201), a traveling neuroscience fellowship from the Program in Interdisciplinary Neuroscience at BWH, and the Women’s Brain Initiative at BWH. EAC acknowledges support from R01NS110942, P01CA163205, P01CA069246, P01CA236749 and DoD WB1XWIH2010017. DAR acknowledges support from the Jennifer Oppenheimer Cancer Research Initiative, the Ben and Catherine Ivy Foundation, and PO1CA236749.
The authors declare no competing interests.
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Adult Astrocyte RNA-Seq Explorer: http://astrocyternaseq.org
Brain Immune Atlas: http://www.brainimmuneatlas.org
Brain TIME: https://joycelab.shinyapps.io/braintime
Glioma Microglia RNA Expression: http://www.glioma-microglia.com
Myeloid Single-cell RNA-Seq: https://myeloidsc.appspot.com
Single Cell Portal at the Broad Institute: https://singlecell.broadinstitute.org/single_cell/study/SCP393/single-cell-rna-seq-of-adult-and-pediatric-glioblastoma
UCSC Cell Browser: http://gbm.cells.ucsc.edu
- Brain tumour microenvironment
(TME). The dynamic, heterogeneous mixture of extracellular matrix and malignant and non-malignant cells, including neurons, glia, leukocytes and endothelial cells, that make up the gross brain tumour mass. Half or more of the cells within the brain tumour microenvironment, in particular in glioma, are non-neoplastic.
- Cell types
The stable identities of cells, primarily defined by intrinsic gene expression programmes, which contain permanent traits, including the potential to express certain genes and exert certain functions in response to external signals.
- Cell states
Within cell types, states are defined by the current gene expression, metabolic or functional conditions, which are a product of external signals from infection, inflammation, ageing or other disease. The duration of each cell state may be a function of ongoing signalling.
CNS-resident phagocytic cells primarily derived from the yolk sac with multiple roles in the development of disease, including synapse, surveillance and cell debris engulfment, cytokine production, and cross-talk with astrocytes and oligodendrocytes.
- Multi-omic studies
Approaches that include the quantification and characterization of data from various molecular domains such as the genome, transcriptome, proteome, metabolome and epigenome.
- Isocitrate dehydrogenase
(IDH1 or IDH2). Enzymes in the tricarboxylic acid cycle that catalyse the decarboxylation of isocitrate, producing alpha-ketoglutarate and carbon dioxide. Some mutations in IDH lead to the production of 2-hydroxyglutarate, a metabolite whose accumulation leads to genomic instability of glial cells through DNA methylation.
One of the four transcriptional meta-signatures of GBM defined by bulk RNA sequencing featuring loss of neurofibromin 1 (NF1) expression and increased expression of mesenchymal-related, hypoxia-response, stress and glycolytic genes. It was associated with increased tumour-associated macrophage infiltration and a more immunosuppressive tumour-associated macrophage phenotype, suggesting its relevance for tumour–tumour microenvironment cross-talk.
- Extracellular membrane particles
Subcellular particles shed from malignant or non-malignant cells that are composed of a lipid bilayer with variable size and cargo, including proteins, metabolites and nucleic acids. Communication with neighbouring and sometimes distant cells is possible through their contents.
- Mass cytometry
A cytometric technique that quantifies protein expression at the single-cell level by combining the use of rare earth metal isotope-conjugated antibodies and cytometry by time of flight (CyTOF).
- Cellular indexing of transcriptomes and epitopes by sequencing
(CITE-seq). Combining DNA barcode-conjugated antibody labelling with single-cell RNA sequencing to enable immunophenotyping and unbiased transcriptome analysis.
- Blood–brain barrier
A variety of features specific to brain vasculature that limit the influx of chemicals or immune cells in addition to the active efflux of chemical molecules, thereby limiting neurotoxicity.
- Myeloid-derived suppressor cells
(MDSCs). A heterogeneous group of immature myeloid cells that contain monocyte-like and granulocyte-like subsets, which inhibit anti-tumour T cell responses through ARG1, IL-10 and TGFβ.
An extracellular enzyme that can be membrane bound or secreted.
- Blood–tumour barrier
Heterogeneous impairment of the blood–brain barrier and the interface between the blood and tumour due to tissue destruction by tumour growth and neoangiogenesis, resulting in altered but not necessarily efficient penetration of drug molecules and immune molecules.
The origins and development of specific cell types.
- Proneural subtype of GBM
One of four subtypes defined by bulk RNA sequencing of GBM through the Cancer Genome Atlas (TCGA), characterized by elevated expression of PDGFRA and CDK4. Originally, it was thought that each tumour represents a distinct subtype, but single-cell RNAseq of GBM revealed that all four subtypes can be detected within each tumour with varying proportions. More recently, the proneural subtype has been hypothesized to coincide with the oligodendrocyte-like and neural progenitor-like cellular states identified by single-cell RNA sequencing.
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Andersen, B.M., Faust Akl, C., Wheeler, M.A. et al. Glial and myeloid heterogeneity in the brain tumour microenvironment. Nat Rev Cancer 21, 786–802 (2021). https://doi.org/10.1038/s41568-021-00397-3
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