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IFN-gamma-dependent tissue immune homeostasis is co-opted in the tumor microenvironment

ABSTRACT: Homeostatic programs maintain equilibrium between immune protection, and selftolerance. Such mechanisms impact autoimmunity and tumor formation, respectively. How tissue homeostasis is maintained, and impacts tumor surveillance is unknown. Here we identify that mononuclear phagocytes share conserved programming during homeostatic differentiation, and entry into tissue. IFNγ is necessary and sufficient to induce these transcripts, revealing a key instructive role. Remarkably, homeostatic and IFNγ-dependent programs enrich across primary human tumors, including melanoma, and stratify metastatic melanoma survival. Single-cell RNA-sequencing reveals enrichment of these modules in monocytes and DCs in human metastatic melanoma. Suppressor-of-cytokine-2 (SOCS2), a highly conserved transcript in this program is induced by IFNγ, and expressed in mononuclear phagocytes infiltrating primary melanoma. SOCS2 limits DC adaptive anti-tumoral immunity and T cell priming in vivo, indicating a critical regulatory role. Our findings link homeostasis in peripheral tissue to anti-tumoral immunity and escape, revealing coopting of tissue-specific immune development in the tumor microenvironment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE100050 | GEO | 2017/06/27

SECONDARY ACCESSION(S): PRJNA390553

REPOSITORIES: GEO

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IFNγ-dependent tissue immune homeostasis is co-opted in the tumor microenvironment

Project description:Homeostatic programs maintain equilibrium between immune protection, and selftolerance. Such mechanisms impact autoimmunity and tumor formation, respectively. How tissue homeostasis is maintained, and impacts tumor surveillance is unknown. Here we identify that mononuclear phagocytes share conserved programming during homeostatic differentiation, and entry into tissue. IFNγ is necessary and sufficient to induce these transcripts, revealing a key instructive role. Remarkably, homeostatic and IFNγ-dependent programs enrich across primary human tumors, including melanoma, and stratify metastatic melanoma survival. Single-cell RNA-sequencing reveals enrichment of these modules in monocytes and DCs in human metastatic melanoma. Suppressor-of-cytokine-2 (SOCS2), a highly conserved transcript in this program is induced by IFNγ, and expressed in mononuclear phagocytes infiltrating primary melanoma. SOCS2 limits DC adaptive anti-tumoral immunity and T cell priming in vivo, indicating a critical regulatory role. Our findings link homeostasis in peripheral tissue to anti-tumoral immunity and escape, revealing coopting of tissue-specific immune development in the tumor microenvironment. The raw FASTQ sequence files are being deposited in dbGAP.

2017-06-29 | GSE100337 | GEO

IFN-gamma-dependent tissue immune homeostasis is co-opted in the tumor microenvironment

Project description:Homeostatic programs maintain equilibrium between immune protection, and selftolerance. Such mechanisms impact autoimmunity and tumor formation, respectively. How tissue homeostasis is maintained, and impacts tumor surveillance is unknown. Here we identify that mononuclear phagocytes share conserved programming during homeostatic differentiation, and entry into tissue. IFNγ is necessary and sufficient to induce these transcripts, revealing a key instructive role. Remarkably, homeostatic and IFNγ-dependent programs enrich across primary human tumors, including melanoma, and stratify metastatic melanoma survival. Single-cell RNA-sequencing reveals enrichment of these modules in monocytes and DCs in human metastatic melanoma. Suppressor-of-cytokine-2 (SOCS2), a highly conserved transcript in this program is induced by IFNγ, and expressed in mononuclear phagocytes infiltrating primary melanoma. SOCS2 limits DC adaptive anti-tumoral immunity and T cell priming in vivo, indicating a critical regulatory role. Our findings link homeostasis in peripheral tissue to anti-tumoral immunity and escape, revealing coopting of tissue-specific immune development in the tumor microenvironment. To test if IFN-gamma is not only sufficient, but also necessary to condition DC, we compared the programing of migDC isolated from the skin draining LNs of IFNgR1-/-, WT, and IL27Ra-/- mice. IL-27Ra mice were included as an additional control for IFN-gamma receptor specificity.

2017-06-29 | GSE98994 | GEO

Affymetrix 250K StyI SNP array data from PBMCs and cell lines of metastatic melanoma patients

Project description:Allele call files from on 250K StyI SNP array using DNA from 60 human cell lines from metastasized melanoma and from 44 corresponding peripheral blood mononuclear cells (CEL and CHP files provided). Analysis of the 250K StyI arrays was performed for 60 malignant melanoma cell lines derived from metastatic tumors of melanoma patients with GCOS and GTYPE (Affymetrix). In addition, DNA from peripheral blood mononuclear cells (PBMC) was available for 44 of the 60 samples.

2010-04-13 | E-GEOD-17534 | biostudies-arrayexpress

1H NMR Metabolomics Study of Metastatic Melanoma in C57BL/6J Mouse Spleen

Project description:Tissue extracts from metastatic melanoma mouse spleen and controls were compared via NMR based metabolomic analysis

2015-01-08 | ST000133 | MetabolomicsWorkbench

Human melanoma cell lines secretome analysis

Project description:The imbalance of cellular homeostasis during oncogenesis together with the high heterogeneity of tumor-associated stromal cells have a marked effect on the repertoire of the proteins secreted by malignant cells (the secretome). Hence, the study of tumoral secretomes provides insights for understanding the cross-talk between cells within the tumor microenvironment as well as the key effectors for the establishment of the pre-metastatic niche in distant tumor sites. In this context, we performed a proteomic analysis of the secretomes derived from four cell lines: (i) a paired set of fibroblasts - Hs 895. T, a cell line obtained from a lung node metastatic site from a patient who had melanoma and Hs 895.Sk, a skin fibroblast cell line (derived from the same patient); (ii) two malignant metastatic melanoma cell lines - A375, a malignant melanoma cell line from primary source and SH-4, a cell line derived from pleural effusion of a patient with metastatic melanoma. Clustering of expression profiles together with functional enrichment revealed patterns that mirrored each cell type (skin fibroblasts, cancer-associated fibroblasts and metastatic cells). These patterns might be the result of cell-specific protein expression programs and may serve as basis for further proteomic analysis of melanoma cell lines secretomes.

2018-01-02 | PXD007265 | Pride

Single-cell transcriptome sequencing of macrophages in acute kidney injury

Project description:We uesd single-cell transcriptome sequencing technology to sequence the mononuclear phagocytes in the mice kidney, blood and spleen after acute kidney injury, and comprehensively describe characteristics of mononuclear phagocytes.

2022-02-09 | GSE174324 | GEO

Gene expression profile of GM-CSF derived bone marrow dendritic cell subsets

2015-02-27 | GSE62361 | GEO

Mononuclear phagocytes in muscle after notexin injury in C57Bl/6, Cx3cr1-/-, Ccl2-/-,Cx3cr1-/-Ccl2-/- mice

Project description:Muscle injury triggers inflammation in which infiltrating mononuclear phagocytes are crucial for tissue regeneration. The interaction of the CCL2/CCR2 and CX3CL1/CX3CR1 chemokine axis that guides phagocyte infiltration is incompletely understood. Here, we show that CX3CR1 deficiency promotes muscle repair and rescues Ccl2-/- mice from impaired muscle regeneration as a result of altered macrophage function, not infiltration. Transcriptomic analysis of muscle mononuclear phagocytes reveals that Apolipoprotein E (ApoE) is up-regulated in mice with efficient regeneration. ApoE treatment enhances phagocytosis by mononuclear phagocytes in vitro, and restores phagocytic activity and muscle regeneration in Ccl2-/- mice. Because CX3CR1 deficiency may compensate for defective CCL2-dependant monocyte recruitment by modulating ApoE-dependent macrophage phagocytic activity, targeting CX3CR1 expressed by macrophages might be a powerful therapeutic approach to improve muscle regeneration.

2015-09-29 | GSE73473 | GEO

Gene expression profile of GM-CSF derived bone marrow dendritic cell subsets after LPS stimulation

Project description:GM-CSF derived bone marrow cultures contain several subsets of CD11c+MHCII+ mononuclear phagocytes Using Affymetrix microarrays we compared gene expression of the different mononuclear phagocytes within the bone marrow culture. The different populations are left unstimulated or are stimulated with LPS

2015-09-01 | GSE62746 | GEO

Gene expression profile of GM-CSF derived bone marrow dendritic cell subsets

Project description:GM-CSF derived bone marrow cultures contain several subsets of CD11c+MHCII+ mononuclear phagocytes Using Affymetrix microarrays we compared gene expression of the different mononuclear phagocytes within the bone marrow culture The Affymetrix GeneChip Mouse Gene 1.0 arrays were used to define gene expression profiles in the different population.

2015-02-27 | E-GEOD-62361 | biostudies-arrayexpress

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