A nonmyeloablative chimeric mouse model accurately defines microglia and macrophage contribution in glioma

Yu, Kenny; Youshani, Amir Saam; Wilkinson, Fiona L.; O’Leary, Claire; Cook, Peter C.; Laaniste, Liisi; Liao, Aiyin; Mosses, Dominic; Waugh, Chris; Shorrock, Hannah K.; Pathmanaban, Omar; MacDonald, Andrew S.; Kamaly-Asl, Ian; Roncaroli, Federico; Bigger, Brian

doi:10.1111/nan.12489

Cited by 20 publications

(21 citation statements)

References 72 publications

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“…The two currently proposed sources of TAMs are bone marrow derived monocytes (BMDM), which reach the tumor through the blood stream, and CNS-resident microglia cells activated locally by the tumor microenvironment. The identification and tracking of these cell pools has been problematic due to the lack of consistent markers, and a number of studies using different models have disagreed upon the relative proportions of each in www.nature.com/scientificreports/ GBM [50][51][52][53] . Our approach uses gene expression programs, rather than single markers, to represent cell identity as a numeric score in order to reflect the biological continuum of in vivo cells.…”

Section: Discussionmentioning

confidence: 99%

Distinct regional ontogeny and activation of tumor associated macrophages in human glioblastoma

Landry

Balas

Alli

et al. 2020

Sci Rep

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Tumor-associated macrophages (TAMs) constitute up to 50% of tumor bulk in glioblastoma (GBM) and play an important role in tumor maintenance and progression. The recently discovered differences between invading tumour periphery and hypoxic tumor core implies that macrophage biology is also distinct by location. This may provide further insight into the observed treatment resistance to immune modulation. We hypothesize that macrophage activation occurs through processes that are distinct in tumor periphery versus core. We therefore investigated regional differences in TAM recruitment and evolution in GBM by combining open source single cell and bulk gene expression data. We used single cell gene expression data from 4 glioblastomas (total of 3589 cells) and 122 total bulk samples obtained from 10 different patients. Cell identity, ontogeny (bone-marrow derived macrophages-BMDM vs microglia), and macrophage activation state were inferred using verified gene expression signatures. We captured the spectrum of immune states using cell trajectory analysis with pseudotime ordering. In keeping with previous studies, TAMs carrying BMDM identity were more abundant in tumor bulk while microglia-derived TAMs dominated the tumor periphery across all macrophage activation states including pre-activation. We note that core TAMs evolve towards a pro-inflammatory state and identify a subpopulation of cells based on a gene program exhibiting strong, opposing correlation with Programmed cell Death-1 (PD-1) signaling, which may correlate to their response to PD-1 inhibition. By contrast, peripheral TAMs evolve towards anti-inflammatory phenotype and contains a population of cells strongly associated with NFkB signaling. Our preliminary analysis suggests important regional differences in TAMs with regard to recruitment and evolution. We identify regionally distinct and potentially actionable cell subpopulations and advocate the need for a multi-targeted approach to GBM therapeutics.

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Section: Discussionmentioning

confidence: 99%

Distinct regional ontogeny and activation of tumor associated macrophages in human glioblastoma

Landry

Balas

Alli

et al. 2020

Sci Rep

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“…Moreover, emerging evidence supports the view that microglia and macrophages colonize different regions of malignant gliomas, such that macrophages appear to be recruited early during tumorigenesis and occupy perivascular regions [Z Chen et al, 2017]. However, conflicting data exist regarding the major monocyte population in these tumors, with some studies reporting a microglia predominance [Hutter et al, 2019] and others demonstrating that infiltrating macrophages represent the majority of the GAM population [Z Chen et al, 2017] [ K Yu et al, 2019]. These differences could reflect specific experimental mouse model systems (RCAS model versus GL261 or T387 cell lines) used in each of these studies, suggesting that variations in GAM populations may be differentially dictated by the molecular properties of the glioma.…”

Section: Glioma Cells Attract/recruit Gammentioning

confidence: 98%

Microglia/Brain Macrophages as Central Drivers of Brain Tumor Pathobiology

Gutmann

Kettenmann

2019

Neuron

217

247

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One of the most common brain tumors in children and adults is the glioma or astrocytoma. There are few effective therapies for these cancers, and patients with malignant glioma fare poorly, even after aggressive surgery, chemotherapy and radiation. Over the past decade, it is now appreciated that these tumors are comprised of numerous distinct neoplastic and non-neoplastic cell populations, which could each influence overall tumor biology and response to therapy. Among these non-cancerous cell types, monocytes (microglia and macrophages) predominate. In this review, we discuss the complex interactions involving microglia and macrophages relevant to glioma formation, progression, and response to therapy.

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“…In addition, the monocyte chemotactic proteins (MCPs), particularly MCP-1/chemokine (C-C motif) ligand 2 (CCL2) [26,27] , and the stromal-derived factor-1 (SDF-1) [28] , have shown to play a role in the recruitment of microglial cells to the tumor site [ Figure 1]. In addition a substantial number of peripherally derived macrophages can be consistently detected in glioma GL261 implanted tumors, since the early phases of disease [29] . Once inside the tumors, GAMs usually acquire a specific phenotype of activation [30] that favors tumor growth, angiogenesis and promotes the invasion of normal brain pa-renchyma [5] .…”

Section: Drugs That Interfere With Gams' Recruitment At the Tumor Sitementioning

confidence: 99%

Glioma associated microglia/macrophages, a potential pharmacological target to promote antitumor inflammatory immune response in the treatment of glioblastoma

Russo¹,

Cappoli²

2018

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Glioma associated microglia/macrophages (GAMs) constitute the largest proportion of glioma infiltrating cells, particularly in high grade tumors (i.e., glioblastoma). Once inside the tumors, GAMs usually acquire a specific phenotype of activation that favors tumor growth, angiogenesis and promotes the invasion of normal brain parenchyma. Therefore, treatments that limit or prevent GAMs' recruitment at the tumor site or modulate their immune activation promoting antitumor activities are expected to exert beneficial effects in glioblastoma. In the present paper, we aim at the revision of pharmacological strategies that interfere with GAMs' function and are currently proposed as an alternative/additional option to current approved cytotoxic regimens.

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A nonmyeloablative chimeric mouse model accurately defines microglia and macrophage contribution in glioma

Abstract: NMT is a powerful method for dissecting tumour microglia and macrophage subpopulations and can guide further investigation of BMDC subsets in glioma and neuro-inflammatory diseases.

Cited by 20 publications

References 72 publications

Distinct regional ontogeny and activation of tumor associated macrophages in human glioblastoma

Distinct regional ontogeny and activation of tumor associated macrophages in human glioblastoma

Microglia/Brain Macrophages as Central Drivers of Brain Tumor Pathobiology

Glioma associated microglia/macrophages, a potential pharmacological target to promote antitumor inflammatory immune response in the treatment of glioblastoma

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