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Microglia promote glioblastoma growth via mTOR-mediated immunosuppressive conditioning of the tumor microenvironment.

ABSTRACT: Microglia promote glioblastoma growth via mTOR-mediated immunosuppressive conditioning of the tumor microenvironment.

PROVIDER: PRJNA613838 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11363343_1.fastq.gz	Fastqsanger.gz
	SRR11363343_2.fastq.gz	Fastqsanger.gz
	SRR11363344_1.fastq.gz	Fastqsanger.gz
	SRR11363344_2.fastq.gz	Fastqsanger.gz
	SRR11363345_1.fastq.gz	Fastqsanger.gz

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Microglia promote glioblastoma growth via mTOR-mediated immunosuppressive conditioning of the tumor microenvironment.

Project description:Tumor-associated microglia and macrophages (TAM) are the most numerous non-neoplastic populations in the tumor microenvironment of glioblastoma (GBM), the most common malignant brain tumor in adulthood. The mTOR pathway, an important regulator of cell survival and proliferation, is known to be upregulated in GBM, but little is known about a potential role of this pathway in TAM. Here, we show that GBM-initiating cells (GIC) induce mTOR signalling in TAM-Microglia (TAM-MG) but not TAM-Macrophages (TAM-BMDM) in in vitro and in vivo GBM mouse models. mTOR-dependent regulation of STAT3 and NF-ĸB activity promotes an immunosuppressed phenotype in TAM-MG which hinders effector T cell proliferation and immune reactivity, thereby contributing to tumor immune evasion and promoting tumor growth in a mouse model. The translational value of these results is demonstrated in whole transcriptome datasets of human GBM and in a novel in vitro model whereby IPSC-derived microglia-like cells are conditioned by syngeneic patient-derived GIC. These results raise the possibility that tumor cells might not be the primary target of mTOR inhibition, and TAM-MG should be considered instead.

2020-07-21 | GSE147329 | GEO

Microglia promote glioblastoma via mTOR-mediated immunosuppression of the tumour microenvironment.

Project description:Tumour-associated microglia/macrophages (TAM) are the most numerous non-neoplastic populations in the tumour microenvironment in glioblastoma (GBM), the most common malignant brain tumour in adulthood. The mTOR pathway, an important regulator of cell survival/proliferation, is upregulated in GBM, but little is known about the potential role of this pathway in TAM. Here, we show that GBM-initiating cells (GIC) induce mTOR signalling in TAM-Microglia (TAM-MG) but not TAM-Bone Marrow-derived Macrophages (TAM-BMDM) in both in vitro and in vivo GBM mouse models. mTOR-dependent regulation of STAT3 and NF-?B activity promotes an immunosuppressed phenotype in TAM-MG. This hinders effector T cell infiltration, proliferation, and immune reactivity, thereby contributing to tumour immune evasion and promoting tumour growth in a mouse model. The translational value of our results is demonstrated in whole transcriptome datasets of human GBM and in a novel in vitro model, whereby expanded-potential stem cells (EPSC)-derived microglia-like cells are conditioned by syngeneic patient-derived GIC. These results raise the possibility that TAM-MG could be the primary target of mTOR inhibition, rather than the intrinsic tumour cells in GBM.

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Microglia promote glioblastoma via mTOR-mediated immunosuppression of the tumour microenvironment.

Project description:Tumour-associated microglia/macrophages (TAM) are the most numerous non-neoplastic populations in the tumour microenvironment in glioblastoma multiforme (GBM), the most common malignant brain tumour in adulthood. The mTOR pathway, an important regulator of cell survival/proliferation, is upregulated in GBM, but little is known about the potential role of this pathway in TAM. Here, we show that GBM-initiating cells induce mTOR signalling in the microglia but not bone marrow-derived macrophages in both in vitro and in vivo GBM mouse models. mTOR-dependent regulation of STAT3 and NF-κB activity promotes an immunosuppressive microglial phenotype. This hinders effector T-cell infiltration, proliferation and immune reactivity, thereby contributing to tumour immune evasion and promoting tumour growth in mouse models. The translational value of our results is demonstrated in whole transcriptome datasets of human GBM and in a novel in vitro model, whereby expanded-potential stem cells (EPSC)-derived microglia-like cells are conditioned by syngeneic patient-derived GBM-initiating cells. These results raise the possibility that microglia could be the primary target of mTOR inhibition, rather than the intrinsic tumour cells in GBM.

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Conditioning-1

Project description:Conditioning-1

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Dual Targeting of EGFR and MTOR pathways inhibits glioblastoma growth by modulating the tumor microenvironment

Project description:In the current study we focused on identifying an effective therapeutic regimen for a cohort of human-derived GBM models driven by alterations in the EGFR pathway. Pharmacological testing based on the genomics characteristic of each patient-derived model demonstrated that no single drug is efficacious in inhibiting tumor cell viability in culture. Combining two targeting agents Erlotinib (Tarceva) and MLN0128 (investigational MTOR inhibitor) resulted in effective tumor cell killing across several GBM PDX- derived culture models. Mechanistically, inhibition of p-ERK, p-AKT and RSK pathways underlie the combinatorial drug effects in culture. Using an orthotopic primary-GBM model, we show that the two drugs combined resulted in significant improvement in survival, superior to either drug alone. Microarray RNA profiling of tumor tissues from treated mice showed that the anti-tumor efficacy of co-inhibiting EGFR and MTOR pathways was in part due to modulation of the tumor microenvironment, including downregulation of CCL2 and Periostin, and subsequent inhibition of TAM infiltration in treated tumors.

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TERT activates endogenous retroviruses contributing to immunosuppressive tumour microenvironment I

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TERT activates endogenous retroviruses contributing to immunosuppressive tumour microenvironment II

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TERT activates endogenous retroviruses to promote an immunosuppressive tumour microenvironment

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Human prostate cancer bone metastases have an actionable immunosuppressive microenvironment

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