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GCN2 drives macrophage and MDSC function and immunosuppression in the tumor microenvironment [RNA-Seq]

ABSTRACT: GCN2 drives macrophage and MDSC function and immunosuppression in the tumor microenvironment [RNA-Seq]

PROVIDER: PRJNA588060 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10408500.fastq.gz	Fastqsanger.gz
	SRR10408600.fastq.gz	Fastqsanger.gz
	SRR10408501.fastq.gz	Fastqsanger.gz
	SRR10408601.fastq.gz	Fastqsanger.gz
	SRR10408502.fastq.gz	Fastqsanger.gz

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

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Project description:The purpose of our study was to examine the role of GCN2 in the function of immunosuppressive cells such as tumor associated macrophages and MDSCs. We show that a myeloid lineage specific deletion of GCN2 results in a shift towards a more proinflammatory phenotype of tumor associated macrophages and MDSCs, thereby promoting anti-tumor immunity.

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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-γ 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.

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Project description:The BRAF inhibitor dabrafenib has been reported to activate the integrated stress response (ISR) kinase GCN2, and the therapeutic effect has been partially attributed to GCN2 activation. Since ISR signaling is a key component of myeloid-derived suppressor cell (MDSC) development and function, we measured the effect of dabrafenib on MDSC differentiation and suppressive activity. Our data showed that dabrafenib attenuated MDSC ability to suppress T cell activity, which was associated with a GCN2-dependent block of the transition from monocytic progenitor to polymorphonuclear (PMN)-MDSCs and proliferative arrest resulting in PMN-MDSC loss. Transcriptional profiling revealed that dabrafenib-driven GCN2 activation altered metabolic features in MDSCs enhancing oxidative respiration, and attenuated transcriptional programs required for PMN development. Thus, ourdata reveals transcriptional networks that govern MDSC developmental programs, and the impact of GCN2 stress signaling on the innate immune landscape in tumors, providing novel insight into potentially beneficial off target effects of dabrafenib.

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

Project description:This SuperSeries is composed of the SubSeries listed below.

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Dabrafenib alters MDSC differentiation and function by activation of GCN2

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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.

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