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Apolipoprotein A1-Manipulated Cholesterol Efflux Subverts the Phagocytic Fragility of TAMs and Improves Oncolytic Viro-Immunotherapy in Glioblastoma [Tumor RNA-seq]

ABSTRACT: We found that overexpression of APOA1 in glioblastoma (GBM) promotes cholesterol efflux from TAMs and restores phagocytosis and antigen presentation. Therefore, we constructed a recombinant oncolytic adenovirus expressing APOA1 to carry the cholesterol regulatory elements of TAMs. AdV-APOA1 exhibited better antitumor effects than AdV-Ctrl in several orthotopic GBM tumor models. Further, we collected virus-treated GL261-CAR tumors for RNA-seq to reveal differences in biological processes between them. Specifically, intracranial 14-day GL261-CAR-bearing C57BL/6J mice were i.t. injected with 1 × 108 PFU AdV-Ctrl or 1 × 108 PFU AdV-APOA1. The tumor bulks were then collected to perform transcriptome RNA-seq analysis 3 days after virus injection.

ORGANISM(S): Mus musculus

PROVIDER: GSE201976 | GEO | 2022/05/04

REPOSITORIES: GEO

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Apolipoprotein A1-Manipulated Cholesterol Efflux Subverts the Phagocytic Fragility of TAMs and Improves Oncolytic Viro-Immunotherapy in Glioblastoma [BMDMs RNA-seq]

Project description:We found that TAMs in the glioblatoma (GBM) tumor microenvironment are enriched for cholesterol and highly express ABCA1/G1. To investigate the biological effects of enhancing cholesterol efflux of TAMs in GBM, we constructed APOA1-overexpressing GL261 cell line. We harvested tumor tissue and sorted these TAMs by anti-mouse F4/80 magnetic beads 17 days after intracranial transplantation of GL261-APOA1 cell line and control cells in immunocompetent C57 mice. Samples were subjected to transcriptome sequencing.

2022-10-09 | GSE214907 | GEO

Apolipoprotein A1-Manipulated Cholesterol Efflux Subverts the Phagocytic Fragility of TAMs and Improves Oncolytic Viro-Immunotherapy in Glioblastoma [TAMs RNA-seq]

2022-05-04 | GSE201975 | GEO

Tumour-associated microglia/macrophages in Glioblastoma are heterogenous and display higher immunological reactivity under aconitate decarboxylase 1 deficiency

Project description:In Glioblastoma (GBM), tumour-associated microglia/macrophages (TAMs) represent the most abundant cells of the stromal compartment contributing to tumour immune escape mechanisms. Thus, strategies targeting TAMs are emerging as promising objectives for immunotherapy. However, TAMs heterogeneity is only starting to emerge and little is known about their contribution to GBM progression. Here, we comprehensively study the molecular changes of TAMs in the GL261 GBM mouse model by single-cell RNA-sequencing across GBM progression and in the absence of Acod1/Irg1, a key gene involved in macrophage metabolic reprogramming. We identify distinct TAM profiles, mainly based on their ontogeny, which recapitulate microglia- versus macrophage-like features showing key transcriptional differences and rapidly adapting along GBM stages. Notably, we uncover a decreased antigen-presenting cell signature in TAMs along tumour progression that is less prominent in Acod1/Irg1-deficient mice. Overall, our results provide insights into TAMs heterogeneity and highlight a potential role for Acod1/Irg1 in TAMs polarization along GBM progression.

2020-09-16 | GSE158016 | GEO

Manipulating Cholesterol Metabolism by oncolytic virus suppresses metastasis of triple-negative breast cancer [tumors]

Project description:To investigate the effect of ADV or AAV encoding ApoA1 treatment on the gene expression of 4T1 tumor in vivo

2022-05-10 | GSE202426 | GEO

RNA-seq of co-culture experiment between human HUVEC endothelial cells and mouse glioma GL126 cells

Project description:Increased awareness for the role for angiocrine factors in stem cell biology, in general, has suggested a role for angiocrine factors in the maintenance of GSC stemness and also there are reciprocal bi-directional signals from endothelial cells (ECs) to glioma (Gl261) and vice versa. To extend, refine and elucidate perfusion-independent modes of GBM-EC communication (i.e., distinguishing contact dependent or contact independent routes), we carried-out the following experiments: ECs from umbilical veins tagged with RFP (HUVEC-RFP) were cultured with mouse glioma line Gl261 fluorescently labelled with GFP (Gl261-GFP) until reaching confluency by 72 h post culturing. Cells were than harvested, RNA extracted, and the combined co-culture transcriptomes were sequenced from a generated cDNA library without prior separation of the respective cell types (sample named as Co). The Co transcriptome was compared to that of an artificial mixtures of the two cell types (Gl261-GFP and HUVEC-RFP) in the exact cells ratio attained by the end of the co-cluttering aided by FACS-based determination of the GFP/RFP ratio (Gl261:HUVEC - 3:1) attained by the end of the co-cluttering aided by FACS-based determination of the GFP/RFP ratio (sample named as Sep). In this procedure advantage was taken on the different species from which GBM and EC are derived and specialized bioinformatics tools allowing to unambiguously assign the transcripts to their respective GBM (mouse) or EC (human) origins, thereby circumventing confounding factors associated with cell purification

2022-04-01 | E-MTAB-9610 | biostudies-arrayexpress

Manipulating Cholesterol Metabolism by oncolytic virus suppresses metastasis of triple-negative breast cancer [cell line]

Project description:To investigate the effect of ApoA1 mediated cholesterol efflux on the gene expression of 4T1 cells

2022-05-10 | GSE202427 | GEO

RNA-seq of co-culture experiment between human endothelial cells (HUVECs) and mouse glioma (Gl261) with or without Notch Inhibitor Gamma Secretase Inhibitor (GSI)

Project description:Increased awareness for the role for angiocrine factors in stem cell biology, in general, has suggested a role for angiocrine factors in the maintenance of GSC stemness and also there are reciprocal bi-directional signals from endothelial cells (ECs) to glioma (Gl261) and vice versa. To extend, refine and elucidate perfusion-independent modes of GBM-EC communication (i.e., distinguishing contact dependent or contact independent routes), we carried-out the following experiments: ECs from umbilical veins tagged with RFP (HUVEC-RFP) were cultured with mouse glioma line Gl261 fluorescently labelled with GFP (Gl261-GFP) until reaching confluency by 72 h post culturing. Cells were than harvested, RNA extracted, and the combined co-culture transcriptomes were sequenced from a generated cDNA library without prior separation of the respective cell types (sample named as Co). The Co transcriptome was compared to that of an artificial mixtures of the two cell types (Gl261-GFP and HUVEC-RFP) in the exact cells ratio attained by the end of the co-cluttering aided by FACS-based determination of the GFP/RFP ratio (sample named as Sep). In this procedure advantage was taken on the different species from which GBM and ECs are derived and specialized bioinformatics tools allowing to unambiguously assign the transcripts to their respective GBM (mouse) or EC (human) origins, thereby circumventing confounding factors associated with cell purification. Considering that contact-dependent EC signaling is primarily regulated by canonical Notch pathway and that the Notch pathway was reported to play a role in self-renewal of GSCs, we also treated GBM-EC co-cultures with the Notch pathway inhibitor Gamma secretase inhibitor (GSI) (or with the DMSO vehicle alone) for 24 h before harvesting.

2022-01-01 | E-MTAB-9604 | biostudies-arrayexpress

STING activation promotes robust immune response and NK cell- mediated tumor regression in glioblastoma models

Project description:Immunotherapy has had a tremendous impact on cancer treatment in the past decade, with hitherto unseen responses at advanced and metastatic stages of the disease. However, the aggressive brain tumor glioblastoma (GBM) is highly immunosuppressive and remains largely refractory to current immunotherapeutic approaches. The cGAS-STING cytoplasmic double stranded DNA (dsDNA) sensing pathway has emerged as a next-generation immunotherapy target with potent local immune stimulatory properties. Here, we investigated the status of the STING pathway in GBM and the modulation of the brain tumor microenvironment (TME) with the STING agonist ADU-S100. Our data reveal the presence of STING in human GBM specimens, where it stains strongly in the tumor vasculature. We show that human GBM explants can respond to STING agonist treatment by secretion of inflammatory cytokines. In murine GBM models, we show a profound shift in the tumor immune landscape after STING agonist treatment, with massive infiltration of the tumor-bearing hemisphere with innate immune cells including inflammatory macrophages, neutrophils and NK populations. Treatment of established murine intracranial GL261 and CT-2A tumors by biodegradable ADU-S100-loaded intracranial implants demonstrated a significant increase in survival in both models and long-term survival with immune memory in GL261. Responses to treatment were abolished by NK cell depletion. This study reveals therapeutic potential and deep remodeling of the TME by STING activation in GBM and warrants the further examination of STING agonists alone or in combination with other immunotherapies such as cancer vaccines, CAR T cells, NK therapies or immune checkpoint blockade.

2022-06-28 | GSE206604 | GEO

CSF-1R inhibition alters macrophage polarization and blocks gliomagenesis

Project description:Glioblastoma multiforme (GBM), the most common and aggressive primary brain tumor in adults, can be divided into several molecular subtypes including proneural GBM. Most clinical strategies aimed at directly targeting glioma cells in these tumors have failed. A promising alternative is to target stromal cells in the brain microenvironment, such as tumor-associated microglia and macrophages (TAMs). Macrophages are dependent upon colony stimulating factor (CSF)-1 for differentiation and survival; therefore, we used an inhibitor of its receptor, CSF-1R, to target macrophages in a mouse proneural GBM model. CSF-1R inhibition dramatically increased survival in mice and regressed established GBMs. Tumor cell apoptosis was significantly increased, and proliferation and tumor grade markedly decreased. Surprisingly, TAMs were not depleted in tumors treated with the CSF-1R inhibitor. Instead, analysis of gene expression in TAMs isolated from treated tumors revealed a decrease in alternatively activated/ M2 macrophage markers, consistent with impaired tumor-promoting functions. These gene signatures were also associated with better survival specifically in the proneural subtype of patient gliomas. Collectively, these results establish macrophages as valid therapeutic targets in proneural gliomas, and highlight the clinical potential for CSF-1R inhibitors in GBM. RNA was isolated from sorted tumor associated macrophages (TAMs) from murine gliomas following either 7 days of vehicle or BLZ945 treatment. Samples were collected from 16 total tumor burdened mice, with 8 replicates for each treatment group. BLZ945: a Colony-Stimulating Factor 1 Receptor (CSF-1R) inhibitor

2013-09-20 | E-GEOD-37475 | biostudies-arrayexpress

Spatiotemporal single-cell transcriptomics in mouse and human to investigate TAM evolution during GBM progression

Project description:Glioblastoma (GBM) is the most common and malignant primary brain tumor. Although immunotherapy has shown promise in certain cancer types, it has not been effective against GBM, largely due to its highly immunosuppressive tumor microenvironment (TMEs), which is rich in tumor-associated macrophages/microglia (TAMs). TAMs in late-stage GBM contribute to T-cell exhaustion and worsen prognosis, but the role of TAMs in earlier stages of tumor development is unclear. By employing genetically engineered mouse models and human samples, we used spatiotemporal single-cell transcriptomics to investigate TAM evolution during GBM progression.

2023-09-06 | GSE241037 | GEO

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