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Brain metastasis from EGFR-mutated non-small cell lung cancer: Secretion of IL11 from astrocytes up-regulates PDL1, increases apoptosis of T lymphocytes, and promotes immune escape.

ABSTRACT: Brain metastasis from EGFR-mutated non-small cell lung cancer: Secretion of IL11 from astrocytes up-regulates PDL1, increases apoptosis of T lymphocytes, and promotes immune escape.

PROVIDER: PRJNA1011294 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25845040_1.fastq.gz	Fastqsanger.gz
	SRR25845040_2.fastq.gz	Fastqsanger.gz
	SRR25845041_1.fastq.gz	Fastqsanger.gz
	SRR25845041_2.fastq.gz	Fastqsanger.gz
	SRR25845042_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Brain metastasis from EGFR-mutated non-small cell lung cancer: Secretion of IL11 from astrocytes up-regulates PDL1, increases apoptosis of T lymphocytes, and promotes immune escape.

Project description:To investigatethe mechanism responsible for the astrocyte-induced upregulation of PDL1 in BM cells, we constructed the tumor cell-astrocyte co-culture system.

2024-03-23 | GSE242073 | GEO

Brain Metastasis from EGFR-Mutated Non-Small Cell Lung Cancer: Secretion of IL11 from Astrocytes Up-Regulates PDL1 and Promotes Immune Escape.

Project description:Patients who have non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations are more prone to brain metastasis (BM) and poor prognosis. Previous studies showed that the tumor microenvironment of BM in these patients is immunosuppressed, as indicated by reduced T-cell abundance and activity, although the mechanism of this immunosuppression requires further study. This study shows that reactive astrocytes play a critical role in promoting the immune escape of BM from EGFR-mutated NSCLC by increasing the apoptosis of CD8+ T lymphocytes. The increased secretion of interleukin 11(IL11) by astrocytes promotes the expression of PDL1 in BM, and this is responsible for the increased apoptosis of T lymphocytes. IL11 functions as a ligand of EGFR, and this binding activates EGFR and downstream signaling to increase the expression of PDL1, culminating in the immune escape of tumor cells. IL11 also promotes immune escape by binding to its intrinsic receptor (IL11Rα/glycoprotein 130 [gp130]). Additional in vivo studies show that the targeted inhibition of gp130 and EGFR suppresses the growth of BM and prolongs the survival time of mice. These results suggest a novel therapeutic strategy for treatment of NSCLC patients with EGFR mutations.

| S-EPMC11234401 | biostudies-literature

IL11 is elevated in systemic sclerosis and IL11-dependent ERK signaling is needed for the profibrotic activity of TGFβ in dermal fibroblasts

Project description:Objectives: Interleukin 11 (IL11) is highly upregulated in skin and lung fibroblasts from patients with systemic sclerosis (SSc). Here we tested whether IL11 is mechanistically linked with human dermal fibroblast (HDF) activation. Methods: We measured serum IL11 levels in healthy volunteers and patients with early diffuse SSc and manipulated IL11 signalling in HDFs using gain- and loss-of-function approaches. Results: In patients with SSc, serum IL11 levels are elevated as compared to healthy controls. Transforming growth factor beta (TGFβ) isoforms 1, 2 or 3 induced IL11 secretion from HDFs, which highly express IL11RA and the gp130 co-receptor, suggestive of an autocrine loop of IL11 activity in HDFs. IL11 consistently and robustly stimulated ERK activation in HDFs and resulted in HDF-to-myofibroblast transformation. IL11 induced STAT phosphorylation to a lesser extent than ERK and only at high IL11 concentrations. IL11-stimulated ERK activation and fibrosis phenotypes were absent in skin fibroblasts from patients with homozygous loss-of-function mutation in IL11RA. Inhibition of IL11 signaling using either a neutralizing antibody against IL11 or siRNA against IL11RA reduced TGFβ-induced HDF proliferation, matrix production and cell migration, which was phenocopied by pharmacologic inhibition of ERK activity. Conclusions: These data reveal an important contribution of IL11-related ERK activity for TGFβ-stimulated fibrosis phenotypes in HDFs and suggest IL11 as a potential therapeutic target in SSc.

2021-02-22 | GSE162966 | GEO

Smart-seq II Sequencing Analysis of Pdl1+ and Pdl1- mammary gland basal cell Transcriptomes

Project description:Purpose:Smart sequencing (NGS) has revolutionized systems-based analysis of cellular pathways. The goals of this study are to compare gene expression of Pdl1+ and Pdl1- mammary gland basal cell analysis.Methods:Pdl1+ and Pdl1- mammary gland basal cell mRNA profiles of wild-type (WT) were generated by deep sequencing, in triplicate, using Illumina nova seq. The sequence reads that passed quality filters were analyzed at the transcript isoform level with two methods: Hisat2 as the mapping tool followed byDESeq R package. qRT–PCR validation was performed using TaqMan and SYBR Green assays.Results: Using an optimized data analysis workflow, RNA-seq data confirmed and validated with qRT–PCR.

2021-02-04 | GSE166131 | GEO

Cardiomyocyte-Restricted Expression of IL11 Causes Cardiac Fibrosis, Inflammation, and Dysfunction

Project description:Background: Cardiac fibrosis is a common pathological process in heart disease and represents a therapeutic target. TGFβ is the canonical driver of cardiac fibrosis and was recently shown to be dependent on IL11 for its profibrotic effects in fibroblasts. In the opposite direction, recombinant human IL11 has been reported as anti-fibrotic and also anti-inflammatory in the mouse heart. Objectives: In this study, we determined the effects of IL11 expression in cardiomyocytes on cardiac pathobiology and function. Methods: We used the Cre-loxP system to generate a tamoxifen-inducible mouse with cardiomyocyte-restricted murine Il11 expression. Using protein assays, bulk RNA-sequencing and in vivo imaging we analysed the effects of IL11 on myocardial fibrosis, inflammation and cardiac function and challenge previous reports suggesting cardioprotective potential of IL11. Results: TGFβ stimulation of cardiomyocytes caused Il11 upregulation. As compared to wild-type controls, Il11 expressing hearts demonstrated severe cardiac fibrosis and inflammation that was associated with the upregulation of cytokines, chemokines, complement factors and increased inflammatory cells. IL11 expression also activated a programme of endothelial-to-mesenchymal transition and resulted in left ventricular dysfunction. Conclusion: Our data define species-matched IL11 as strongly profibrotic and proinflammatory when secreted from cardiomyocytes and further establish IL11 as a disease factor.

2023-08-21 | GSE236854 | GEO

Integrated target discovery screens identify IL11 as novel therapeutic target for fibrosis [mouse]

Project description:Cardiac fibrosis is the final common pathology in heart disease. Here we establish an integrated imaging-genomic discovery platform using primary human heart fibroblasts to identify new drug targets for cardiac fibrosis. Genome wide analyses identify IL11, a secreted cytokine amenable to therapeutic inhibition, as the leading pro-fibrotic candidate. We demonstrate an autocrine loop of IL11 activity that is critical for fibrosis and acts as a nexus of signalling convergence for multiple pro-fibrotic stimuli. IL11 signals in cis and trans via the ERK cascade to activate a programme of fibrosis primarily at the level of protein translation. Injection of IL11 to mice causes fibrosis of the heart, kidney, lung, skin and liver whereas genetic ablation of the IL11 receptor prevented fibrosis across tissues. These data define a new non-canonical fibrogenic pathway and prioritise IL11 as a novel therapeutic target for fibrosis of the heart and other organs

2017-11-22 | GSE96991 | GEO

Integrated target discovery screens identify IL11 as novel therapeutic target for fibrosis [human]

2017-11-22 | GSE96975 | GEO

LC-MS/MS Proteomics analysis of PDL1 protein in 293T cell line

Project description:To identify the proteins interact with PDL1 protein in human cell lines, we analyzed the protein complexes using tandem affinity purification followed by mass spectrometry (TAP-MS) in HEK293T. We established the cell lines stably expressing PDL1 gene fused with Flag tags. We identified proteins associated with the bait in the isolated complexes using MS and searched the human databases for these proteins.

2022-10-13 | PXD031702 | Pride

Loss of Lkb1 and Pten Leads to Lung Squamous Cell Carcinoma with Elevated Pdl1 Expression: Stroma Cells

Project description:Lung squamous cell carcinoma (SCC) is a deadly disease for which current treatments are inadequate. We demonstrate that bi-allelic inactivation of Lkb1 and Pten in the mouse lung led to SCC that recapitulated the histology, gene expression and microenvironment found in human disease. Lkb1/Pten-null (LP) tumors expressed the squamous markers Krt5, p63 and Sox2, and transcriptionally resembled the basal subtype of human SCC. In contrast to mouse adenocarcinomas, the LP tumors contained immune populations enriched for tumor-associated neutrophils. Sca1+/Ngfr+ fractions were enriched for tumor propagating cells (TPCs) that could serially transplant the disease in orthotopic assays. TPCs in the LP model and Ngfr+ cells in human SCCs highly expressed Pdl1, suggesting a novel mechanism of immune escape for TPCs. We used microarrays to detail the gene expression profles among lung SCC tumor epitheial cell, lung ADC tumor epithelia cell and normal epithelial cells. Kras tumor stroma cells and LP tumor stroma cells were sorted by FACS, the cells were gated as EpCAM-/CD45+/CD31+

2014-01-24 | E-GEOD-54352 | biostudies-arrayexpress

Loss of Lkb1 and Pten Leads to Lung Squamous Cell Carcinoma with Elevated Pdl1 Expression: Epithelial Cells

Project description:Lung squamous cell carcinoma (SCC) is a deadly disease for which current treatments are inadequate. We demonstrate that bi-allelic inactivation of Lkb1 and Pten in the mouse lung led to SCC that recapitulated the histology, gene expression and microenvironment found in human disease. Lkb1/Pten-null (LP) tumors expressed the squamous markers Krt5, p63 and Sox2, and transcriptionally resembled the basal subtype of human SCC. In contrast to mouse adenocarcinomas, the LP tumors contained immune populations enriched for tumor-associated neutrophils. Sca1+/Ngfr+ fractions were enriched for tumor propagating cells (TPCs) that could serially transplant the disease in orthotopic assays. TPCs in the LP model and Ngfr+ cells in human SCCs highly expressed Pdl1, suggesting a novel mechanism of immune escape for TPCs. We used microarrays to detail the gene expression profles among lung SCC tumor epitheial cell, lung ADC tumor epithelia cell and normal epithelial cells. Normal EpCAM+, Kras tumor EpCAM+ and LP tumor EpCAM+ were sorted by FACS, the cells were gating as EpCAM+/CD45-/CD31-

2014-01-24 | E-GEOD-54351 | biostudies-arrayexpress

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