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Endogenous glucocorticoid signaling regulates effector differentiation and development of dysfunction in CD8+ T cells in the tumor microenvironment

ABSTRACT: Endogenous glucocorticoid signaling regulates effector differentiation and development of dysfunction in CD8+ T cells in the tumor microenvironment

PROVIDER: PRJNA643231 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12118647_1.fastq.gz	Fastqsanger.gz
	SRR12118647_2.fastq.gz	Fastqsanger.gz
	SRR12118648_1.fastq.gz	Fastqsanger.gz
	SRR12118648_2.fastq.gz	Fastqsanger.gz
	SRR12118649_1.fastq.gz	Fastqsanger.gz

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Endogenous glucocorticoid signaling regulates effector differentiation and development of dysfunction in CD8+ T cells in the tumor microenvironment

Project description:Identifying signals in the tumor microenvironment (TME) that shape CD8+ T cell phenotype can inform novel therapeutic approaches for cancer. Here, we identified a gradient of increasing glucocorticoid receptor (GR) expression and signaling from naive to dysfunctional CD8+ tumor-infiltrating lymphocytes (TILs). Conditional deletion of the GR in CD8+ TILs resulted in improved effector differentiation, reduced TCF-1 expression, and failure to develop dysfunctional phenotype, culminating in tumor growth inhibition. GR signaling transactivated the expression of multiple checkpoint receptors and promoted the induction of several dysfunction-associated genes upon T cell activation. In the TME, monocyte/macrophages produced glucocorticoids and genetic ablation of steroidogenesis in these cells as well localized pharmacologic inhibition of glucocorticoid biosynthesis dramatically improved tumor growth control. Active glucocorticoid signaling further associated with failure to respond to checkpoint blockade in both pre-clinical models and melanoma patients, highlighting the clinical relevance of targeting endogenous steroid signaling to enhance anti-tumor T cell responses.

2020-07-01 | GSE153556 | GEO

Endogenous glucocorticoid rhythms regulate the circadian sensitivity to noise

Project description:Endogenous glucocorticoid rhythms regulate the circadian sensitivity to noise

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Dysfunction of S100A4+ effector memory CD8+ T cells aggravates asthma

Project description:Progressive loss of effector functions, especially IFN-γ secreting capability, in effector memory CD8+ T (CD8+ TEM) cells plays a causal role in asthma worsening. However, the mechanisms of CD8+ TEM cell dysfunction remain elusive. Here, we report that S100A4 drives CD8+ TEM cell dysfunction, impairing their protective memory response and promoting asthma worsening in OVA-induced asthma model. We find that allergic CD8+ TEM cells contain two subsets based on S100A4 expression. S100A4+ subsets exhibit dysfunctional effector phenotypes with increased proliferative capability, whereas S100A4- subsets retain effector function but are more inclined to apoptosis, giving rise a dysfunctional CD8+ TEM cell pool. Mechanistically, S100A4 upregulation of mitochondrial metabolism results in a decrease of acetyl-CoA levels, which impair the transcription of effector genes, especially ifn-γ, facilitating cell survival, tolerance and memory potential. Our findings thus reveal general insights into how S100A4 reprograms CD8+ TEM cells into dysfunctional and less protective phenotypes to promote asthma worsening.

2022-03-11 | GSE162116 | GEO

Dysfunction of S100A4+ effector memory CD8+ T cells aggravates asthma

Project description:Dysfunction of S100A4+ effector memory CD8+ T cells aggravates asthma

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TERT activates endogenous retroviruses to promote an immunosuppressive tumour microenvironment

Project description:TERT activates endogenous retroviruses to promote an immunosuppressive tumour microenvironment

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TERT activates endogenous retroviruses contributing to immunosuppressive tumour microenvironment III

Project description:TERT activates endogenous retroviruses contributing to immunosuppressive tumour microenvironment III

| PRJNA717753 | ENA

TERT activates endogenous retroviruses contributing to immunosuppressive tumour microenvironment I

Project description:TERT activates endogenous retroviruses contributing to immunosuppressive tumour microenvironment I

| PRJNA717750 | ENA

TERT activates endogenous retroviruses contributing to immunosuppressive tumour microenvironment II

Project description:TERT activates endogenous retroviruses contributing to immunosuppressive tumour microenvironment II

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Endogenous Glucocorticoid Signaling Regulates CD8<sup>+</sup> T Cell Differentiation and Development of Dysfunction in the Tumor Microenvironment.

Project description:Identifying signals in the tumor microenvironment (TME) that shape CD8+ T cell phenotype can inform novel therapeutic approaches for cancer. Here, we identified a gradient of increasing glucocorticoid receptor (GR) expression and signaling from naïve to dysfunctional CD8+ tumor-infiltrating lymphocytes (TILs). Conditional deletion of the GR in CD8+ TILs improved effector differentiation, reduced expression of the transcription factor TCF-1, and inhibited the dysfunctional phenotype, culminating in tumor growth inhibition. GR signaling transactivated the expression of multiple checkpoint receptors and promoted the induction of dysfunction-associated genes upon T cell activation. In the TME, monocyte-macrophage lineage cells produced glucocorticoids and genetic ablation of steroidogenesis in these cells as well as localized pharmacologic inhibition of glucocorticoid biosynthesis improved tumor growth control. Active glucocorticoid signaling associated with failure to respond to checkpoint blockade in both preclinical models and melanoma patients. Thus, endogenous steroid hormone signaling in CD8+ TILs promotes dysfunction, with important implications for cancer immunotherapy.

| S-EPMC7682805 | biostudies-literature

Hes1 and Liver Glucocorticoid Signaling

Project description:To investigate the role of HES1 during glucocorticoid signaling in the liver, we employed whole-genome microarray expressions in liver mRNA extracted from control and Hes1-liver knockout male mice (HESKOL) that had been adrenalectomized to remove endogenous glucocorticoids. RNA isolated from the liver of control and HESKOL animals either untreated or treated with 1mg/kg of synthetic glucocorticoid (dexamethasone) for 6hours. Each group had an n of 3 mice.

2014-01-08 | E-GEOD-52106 | biostudies-arrayexpress

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