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ARID1A loss shapes immunosuppression tumor microenvironment via NF-kB induced MDSC chemotaxis to promote prostate Cancer metastasis

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE197688 | GEO | 2022/11/07

REPOSITORIES: GEO

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ARID1A loss shapes immunosuppression tumor microenvironment via NF-kB induced MDSC chemotaxis to promote prostate Cancer metastasis [RNA-seq]

Project description:Chronic inflammation and immunosuppressive microenvironment promote prostate cancer (PCa) metastasis and diminish the responses to immune checkpoint blockade (ICB) therapies. However, it remains unclear how and to what extent these two events are coordinated. Here we show that ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, functions downstream of inflammation induced IKKb activation to shape immunosuppressive tumor microenvironment (TME). Prostate-specific deletion of Arid1a cooperates with Pten loss to produce a metastasis-prone tumors. We identify that polymorphonuclear myeloid-derived suppressor cells (MDSCs) as the major infiltrating immune cell type to cause immune evasion, and neutralization of MDSCs restricts metastasis of Arid1a deficient tumors. Mechanistically, inflammation cues activate IKKβ to phosphorylate ARID1A, leading to its degradation via b-TRCP. ARID1A downregulation in turn silences the enhancer of A20 deubiquitinase, a critical negative regulator of NF-kB signaling, and thereby unleashing CXCR2 ligands-mediated MDSC chemotaxis. Importantly, our results support the therapeutic strategy of anti-NF-kB or CXCR2 combined with ICB for advanced PCa. Together, our findings highlight a critical role of ARID1A in MDSCs recruitment and demonstrate IKKb/ARID1A/NF-kB feedback axis integrating inflammation and the immunosuppression to drive PCa metastasis.

2022-11-07 | GSE197686 | GEO

ARID1A loss shapes immunosuppression tumor microenvironment via NF-kB induced MDSC chemotaxis to promote prostate Cancer metastasis [ChIP-seq]

2022-11-07 | GSE197749 | GEO

ARID1A loss shapes immunosuppression tumor microenvironment via NF-kB induced MDSC chemotaxis to promote prostate Cancer metastasis [ATAC-seq]

2022-11-07 | GSE197687 | GEO

ARID1A loss shapes immunosuppression tumor microenvironment via NF-kB induced MDSC chemotaxis to promote prostate Cancer metastasis [RNA-seq II]

2022-11-07 | GSE213251 | GEO

ARID1A loss shapes immunosuppression tumor microenvironment via NF-kB induced MDSC chemotaxis to promote prostate Cancer metastasis

Project description:ARID1A loss shapes immunosuppression tumor microenvironment via NF-kB induced MDSC chemotaxis to promote prostate Cancer metastasis

| PRJNA811575 | ENA

ARID1A loss shapes immunosuppression tumor microenvironment via NF-kB induced MDSC chemotaxis to promote prostate Cancer metastasis [ChIP-seq]

Project description:ARID1A loss shapes immunosuppression tumor microenvironment via NF-kB induced MDSC chemotaxis to promote prostate Cancer metastasis [ChIP-seq]

| PRJNA811961 | ENA

ARID1A loss shapes immunosuppression tumor microenvironment via NF-kB induced MDSC chemotaxis to promote prostate Cancer metastasis [ATAC-seq]

Project description:ARID1A loss shapes immunosuppression tumor microenvironment via NF-kB induced MDSC chemotaxis to promote prostate Cancer metastasis [ATAC-seq]

| PRJNA811578 | ENA

ARID1A loss shapes immunosuppression tumor microenvironment via NF-kB induced MDSC chemotaxis to promote prostate Cancer metastasis [RNA-seq]

Project description:ARID1A loss shapes immunosuppression tumor microenvironment via NF-kB induced MDSC chemotaxis to promote prostate Cancer metastasis [RNA-seq]

| PRJNA811579 | ENA

ARID1A loss shapes immunosuppression tumor microenvironment via NF-kB induced MDSC chemotaxis to promote prostate Cancer metastasis [RNA-seq II]

Project description:ARID1A loss shapes immunosuppression tumor microenvironment via NF-kB induced MDSC chemotaxis to promote prostate Cancer metastasis [RNA-seq II]

| PRJNA880268 | ENA

GCN2 drives macrophage and MDSC function and immunosuppression in the tumor microenvironment.

Project description:General control nonderepressible 2 (GCN2) is an environmental sensor controlling transcription and translation in response to nutrient availability. Although GCN2 is a putative therapeutic target for immuno-oncology, its role in shaping the immune response to tumors is poorly understood. Here, we used mass cytometry, transcriptomics, and transcription factor-binding analysis to determine the functional impact of GCN2 on the myeloid phenotype and immune responses in melanoma. We found that myeloid-lineage deletion of GCN2 drives a shift in the phenotype of tumor-associated macrophages and myeloid-derived suppressor cells (MDSCs) that promotes antitumor immunity. Time-of-flight mass cytometry (CyTOF) and single-cell RNA sequencing showed that this was due to changes in the immune microenvironment with increased proinflammatory activation of macrophages and MDSCs and interferon-? expression in intratumoral CD8+ T cells. Mechanistically, GCN2 altered myeloid function by promoting increased translation of the transcription factor CREB-2/ATF4, which was required for maturation and polarization of macrophages and MDSCs in both mice and humans, whereas targeting Atf4 by small interfering RNA knockdown reduced tumor growth. Last, analysis of patients with cutaneous melanoma showed that GCN2-dependent transcriptional signatures correlated with macrophage polarization, T cell infiltrates, and overall survival. Thus, these data reveal a previously unknown dependence of tumors on myeloid GCN2 signals for protection from immune attack.

| S-EPMC7201901 | biostudies-literature

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