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TGFß in the microenvironment induces a physiologically occurring immune-suppressive senescent state

ABSTRACT: TGFß in the microenvironment induces a physiologically occurring immune-suppressive senescent state

PROVIDER: PRJNA924741 | ENA |

REPOSITORIES: ENA

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TGFß in the microenvironment induces a physiologically occurring immune-suppressive senescent state

Project description:To define the molecular mechanism responsible for promoting Early- and Deep-senescence, we performed RNA-sequencing of the ß-gal-high E- and D-senescent populations.

2023-08-08 | GSE223037 | GEO

TGF-β in the microenvironment induces a physiologically occurring immune-suppressive senescent state.

Project description:TGF-β induces senescence in embryonic tissues. Whether TGF-β in the hypoxic tumor microenvironment (TME) induces senescence in cancer and how the ensuing senescence-associated secretory phenotype (SASP) remodels the cellular TME to influence immune checkpoint inhibitor (ICI) responses are unknown. We show that TGF-β induces a deeper senescent state under hypoxia than under normoxia; deep senescence correlates with the degree of E2F suppression and is marked by multinucleation, reduced reentry into proliferation, and a distinct 14-gene SASP. Suppressing TGF-β signaling in tumors in an immunocompetent mouse lung cancer model abrogates endogenous senescent cells and suppresses the 14-gene SASP and immune infiltration. Untreated human lung cancers with a high 14-gene SASP display immunosuppressive immune infiltration. In a lung cancer clinical trial of ICIs, elevated 14-gene SASP is associated with increased senescence, TGF-β and hypoxia signaling, and poor progression-free survival. Thus, TME-induced senescence may represent a naturally occurring state in cancer, contributing to an immune-suppressive phenotype associated with immune therapy resistance.

| S-EPMC10187541 | biostudies-literature

Clearance of a senescent macrophage-enriched niche ameliorates tumorigenesis in KRAS-driven murine lung cancer models

Project description:Understanding the important role of the tumour microenvironment on tumour initiation and progression is vital for a comprehensive understanding of cancer biology to design effective treatment strategies. Cellular senescence, while traditionally thought of as a cell autonomous tumour-suppressive response to potentially oncogenic insults, is now appreciated to have paracrine tumour promoting roles. We demonstrate a pro-tumourigenic effect of senescent microenvironmental cells on mouse lung tumour progression. To better understand the characteristics of these pro-tumourigenic senescent cells in the tumour microenvironment, we compare putatively senescent cells (reported by mCherry-expression) and non-senescent cells (mCherry-negative cells) from the lung microenvironment of mice induced to form lung tumours by oncogenic KrasG12D-expression in the lung epithelium. Putatively senescent cells are isolated by FACS, based on mCherry-expression which is expressed under the control of the Cdkn2a (p16) locus using a novel genetically engineered allele (p16FDR/+), along with their non-senescent counterparts for comparison by single cell RNA-sequencing.

2023-06-14 | GSE203447 | GEO

Senescent and myofibroblastic cancer-associated fibroblasts share a contractile phenotype regulated by NOX4 generation of reactive oxygen species in the tumour microenvironment

Project description:Cancer associated fibroblasts characterized by an myofibroblastic phenotype play a major role in the tumour microenvironment, being associated with poor prognosis. We found that this cell population is made in part by senescent fibroblasts in vivo. As senescent fibroblasts and myofibroblasts have been shown to share similar tumour promoting functions in vitro we compared the transcriptosomes of these two fibroblast types and performed RNA-seq of human foetal foreskin fibroblasts 2 (HFFF2) treated with 2ng/ml TGF-beta-1 to induce myofibroblast differentiation or 10Gy gamma irradiation to induce senescence. We isolated RNA 7 days upon this treatments changing the medium 3 days before the RNA extraction. A series of SAM alignment files (named after the sample names, for simplicity) are available under http://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-3101/files/ .

2017-06-01 | E-MTAB-3101 | biostudies-arrayexpress

Immune suppressive landscape in a human esophageal squamous cell carcinoma microenvironment

Project description:Immune suppressive landscape in a human esophageal squamous cell carcinoma microenvironment

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Senescent glia link neuronal mitochondrial dysfunction and lipid droplet accumulation with age

Project description:Senescence is a cellular state linked to aging and age-onset disease across many mammalian species. Acutely, senescent cells promote wound healing and prevent tumor formation; but they are also pro-inflammatory, thus chronically exacerbate tissue decline. While senescent cells are active targets for anti-aging therapy, why these cells form in vivo, how they affect tissue aging, and the impact of their elimination remain unclear. Here we identify naturally-occurring senescent glia in aged Drosophila brains and decipher their origin and influence. Using AP1 activity to screen for senescence, we determine that senescent glia can appear in response to neuronal mitochondrial dysfunction. In turn, senescent glia promote lipid accumulation in non-senescent glia; similar effects are seen in senescent human fibroblasts in culture. Targeting AP1 activity in senescent glia mitigates senescence biomarkers, extends fly life and health span, and prevents lipid accumulation. However, these benefits come at the cost of increased oxidative damage in the brain, and neuronal mitochondrial function remains poor. Altogether, our results map the trajectory of naturally-occurring senescent glia in vivo and indicate that these cells link key aging phenomena: mitochondrial dysfunction and lipid accumulation.

2024-05-24 | GSE263928 | GEO

Ac4c modifications down-regulation in macrophages promotes suppressive tumor microenvironment in HCC

Project description:Ac4c modifications down-regulation in macrophages promotes suppressive tumor microenvironment in HCC

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TAZ facilitates breast tumor growth by promoting an immune-suppressive tumor microenvironment

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Immune suppressive landscape in the human non-small cell lung cancer microenvironment

Project description:Immune suppressive landscape in the human non-small cell lung cancer microenvironment

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Single-cell Transcriptome Analysis Revealed that EGFR Mutation Leads to a Suppressive Tumor Immune Microenvironment in Lung Adenocarcinoma

Project description:We analyzed 40,799 single cells from nine samples and found that in EGFR-mutant LUAD, tumor cells generated an immunosuppressive microenvironment by releasing cytokines to attract suppressive immune cells such as myeloid-derived suppressor cells (MDSCs) directly or indirectly by interacting with macrophages, dendritic cells, or other cell types. By contrast, EGFR wild-type LUAD had a greater ability to recruit immunocompetent T cells such as TRMs and Th1 cells, thus driving a proinflammatory microenvironment.

2022-02-09 | GSE171145 | GEO

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