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Type I Interferon Response in Astrocytes Promotes Brain Metastasis by Enhancing Monocytic Myeloid Cell Recruitment

ABSTRACT: Type I Interferon Response in Astrocytes Promotes Brain Metastasis by Enhancing Monocytic Myeloid Cell Recruitment

PROVIDER: PRJNA930486 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23310592.fastq.gz	Fastqsanger.gz
	SRR23310593.fastq.gz	Fastqsanger.gz
	SRR23310594.fastq.gz	Fastqsanger.gz
	SRR23310595.fastq.gz	Fastqsanger.gz
	SRR23310596.fastq.gz	Fastqsanger.gz

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Type I Interferon Response in Astrocytes Promotes Brain Metastasis by Enhancing Monocytic Myeloid Cell Recruitment

Project description:Cancer metastasis to the brain is a significant clinical problem. Metastasis is the consequence of favorable interactions between invaded cancer cells and the microenvironment. Here, we demonstrate that cancer-activated astrocytes create a sustained low-level activated type I interferon (IFN) microenvironment in brain metastatic lesions. We further confirm that the IFN response in astrocytes facilitate brain metastasis. Mechanistically, IFN signaling in astrocytes activates C-C Motif Chemokine Ligand 2 (CCL2) production, which further increases the recruitment of monocytic myeloid cells. The correlation between CCL2 and monocytic myeloid cells is confirmed in clinical brain metastasis samples. Lastly, genetically or pharmacologically inhibiting C-C Motif Chemokine Receptor 2 (CCR2) significantly reduces brain metastases. Our study clarifies a pro-metastatic effect of type I IFN in the brain even though IFN response has been considered to have anti-tumor effects. Moreover, this work expands our understandings on the interactions between cancer-activated astrocytes and immune cells in brain metastasis.

2023-03-16 | GSE224302 | GEO

Type I interferon response in astrocytes promotes brain metastasis by enhancing monocytic myeloid cell recruitment.

Project description:Cancer metastasis to the brain is a significant clinical problem. Metastasis is the consequence of favorable interactions between invaded cancer cells and the microenvironment. Here, we demonstrate that cancer-activated astrocytes create a sustained low-level activated type I interferon (IFN) microenvironment in brain metastatic lesions. We further confirm that the IFN response in astrocytes facilitates brain metastasis. Mechanistically, IFN signaling in astrocytes activates C-C Motif Chemokine Ligand 2 (CCL2) production, which further increases the recruitment of monocytic myeloid cells. The correlation between CCL2 and monocytic myeloid cells is confirmed in clinical brain metastasis samples. Lastly, genetically or pharmacologically inhibiting C-C Motif Chemokine Receptor 2 (CCR2) reduces brain metastases. Our study clarifies a pro-metastatic effect of type I IFN in the brain even though IFN response has been considered to have anti-tumor effects. Moreover, this work expands our understandings on the interactions between cancer-activated astrocytes and immune cells in brain metastasis.

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Proteomic profiling of interferon-responsive reactive astrocytes in rodent and human

Project description:Astrocytes are a heterogenous population of glial cells that respond to pathological insults or injury by undergoing a profound transformation called reactivity. Reactive astrocytes exhibit distinct, context-dependent cellular, molecular, and functional states that can either help or hinder tissue homeostasis. We recently identified a subtype of reactive astrocytes in the mouse brain called interferon-responsive reactive astrocytes (IRRAs), defined by interferon-responsive genes like Igtp, Ifit3, Oasl, Mx1, Cxcl10, and Gbp2 . To further this transcriptomic definition of IRRAs, we wanted to define the proteomic changes that occur in this sub-state.

2023-03-07 | MSV000091426 | MassIVE

STING agonists drive recruitment and intrinsic type I interferon responses in monocytic lineage cells for optimal anti-tumor immunity

Project description:The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, a sensor of cytosolic DNA, orchestrates the production of proinflammatory cytokines, chemokines, and type I interferons (IFN-Is), thereby contributing to spontaneous tumor surveillance. Intratumoral delivery of synthetic STING agonists induces IFN-I-dependent tumor regression in preclinical cancer models and is being tested clinically. In this study, we investigate the role of monocytic lineage cells (MCs) in response to STING agonist induced IFN-I signaling. We show that CCR2-deficient mice, lacking inflammatory MCs in the periphery, or Lyz2-Cre-IFNAR1fl/fl mice in which IFN-I signaling in monocytes is reduced, exhibit impaired responses to STING agonist therapy of MC38 and/or B16F10 tumors. STING agonist treatment induced CCR5-dependent migration of MCs carrying tumor antigen from the tumor to the lymph nodes. Single-cell RNA sequencing of CD45+ cells from lymph nodes and tumors of mice in which half the hematopoietic cells lack the IFNAR1 (interferon alpha/beta receptor 1) revealed that STING agonist therapy induces intrinsic IFNAR1-dependent acquisition of an inflammatory monocytic cell phenotype distinct from inflammatory classical dendritic cells (cDC) and a reduction in macrophages with a protumor TGFβ/angiogenesis transcriptome. Interleukin (IL)-18-IL-18R1 interaction was the top predicted interaction between monocytic lineage cells and CD8+ T cells or natural killer cells. Blocking IL-18 reduced IFN-γ production by CD8 T cells in lymph nodes and decreased the therapeutic efficacy of STING agonist treatment in Ccr2+/+ but not in Ccr2-/- mice. These findings support a pivotal role for IL-18 producing inflammatory monocytic lineage cells in CD8+ T cell control of melanoma following STING agonist treatment.

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Project description:Monocytic acute myeloid leukemia (AML) responds poorly to current treatments, including venetoclax-based therapy. We conducted in vivo and in vitro CRISPR/Cas9 library screenings using a mouse monocytic AML model, and identified SETDB1 and its binding partners (ATF7IP and TRIM33) as crucial tumor promoters in vivo. The growth-inhibitory effect of Setdb1 depletion in vivo was mainly dependent on NK cell-mediated cytotoxicity. Mechanistically, SETDB1 depletion upregulated interferon-stimulated genes and NKG2D ligands through demethylation of histone H3 Lys9 at the monocyte-specific enhancer regions, thereby enhancing their immunogenicity to NK cells and intrinsic apoptosis. Importantly, these effects were not observed in non-monocytic leukemia cells. We also identified the expression of MNDA and its murine counterpart Ifi203 as biomarkers to predict the sensitivity of each AML to SETDB1 depletion. Our study highlights the critical and selective role of SETDB1 in monocytic AML and underscores its potential as a therapeutic target for current unmet needs.

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STING agonists drive recruitment and intrinsic type I interferon responses in monocytic lineage cells for optimal anti-tumor immunity

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SETDB1 suppresses interferon responses and NK cell-mediated immunosurveillance specifically in monocytic AML: H3K9me3 ChIP-seq of cSAM leukemia cells with Setdb1 depletion [ChIP-seq]

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SETDB1 suppresses interferon responses and NK cell-mediated immunosurveillance specifically in monocytic AML: Gene expression profiles of cSAM leukemia cells with Setdb1 depletion [RNA-seq]

2024-08-03 | GSE266097 | GEO

Batf2 is a regulator of interferon gamma signaling in astrocytes during neuroinflammation

Project description:Astrocytic interferon (IFN)g signaling is associated with reduced neuroinflammation; however, downstream effectors responsible for regulating this protection are unknown. Here we identify an interferon-specific transcription factor, basic leucine zipper ATF-like transcription factor (BATF)2, that plays a key role in modulating the consequences of IFNg signaling in astrocytes. Chromatin immunoprecipitation (ChIP) sequencing revealed that BATF2 binds and prevents the overexpression of interferon regulatory factor (IRF)1 and IRF1 targets such as Caspase-1. We also show that Batf2-/- mice exhibit exacerbated clinical disease severity in a murine model of CNS autoimmunity, and express increased astrocyte-specific IRF1 and Caspase-1, suggesting an amplified interferon response in vivo. Additionally, we demonstrate that BATF2 is expressed primarily in astrocytes within multiple sclerosis lesions and that this expression is co-localized with IRF1. Collectively, our results further support evidence of protective functions for IFNg and implicate BATF2 as a key suppressor of overactive immune signaling in astrocytes during neuroinflammation.

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