Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

C-Rel-dependent monocytes are potent immune suppressor cells in cancer

ABSTRACT: Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of leukocytes that are important for tumorigenesis and tumor immunotherapy. They comprise up to 10% of leukocytes in the blood of tumor patients and their depletion may be required for successful tumor immunotherapy. However, the identity of MDSCs remains obscure, primarily due to their heterogeneity and lack of a known lineage-specific transcription factor specifying their differentiation. Using single-cell transcriptomics and gene knockout approaches, we now describe a subset of murine and human myeloid suppressor cells, named rel-dependent monocytes (rMos), which are programmed by the transcription factor c-Rel of the NF-B family. Unlike MDSCs described previously, the c-Rel-dependent monocytes expressed a high amount of the proinflammatory cytokine IL-1β together with a low level of suppressive molecule arginase 1. Both in vitro and in tumor-bearing mice, these c-Rel+IL-1βhiArg1 monocytes promoted tumor growth by potently suppressing T cell function and showed a strong migratory phenotype, all of which were impaired by c-Rel deficiency or inhibition. Mechanistic studies revealed that c-Rel controlled the expression of monocyte signature genes through a unique transcriptional complex called the c-Rel enhanceosome, and IL-1CCL2 crosstalk between tumor cells and the rel-dependent monocytes maintained the suppressive tumor microenvironment. Thus, c-Rel specifies the development of a suppressive monocyte population and could be selectively targeted for treating cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE205557 | GEO | 2022/06/11

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Expression data (HG-U133 Plus 2.0) from human monocyte-derived cell types (TolDC, M-MDSC, MoDC)

Project description:A better understanding of the mechanisms that induce and drive human suppressive myeloid cells, such as myeloid-derived suppressor cells (MDSCs) and tolerogenic dendritic cells (TolDCs), stimulates therapeutic approaches that intent to restore the immune balance in patients. Here, we compared gene profiles of in vitro generated M-MDSCs to TolDCs in the context of monocytes and monocyte-derived DCs (MoDCs).

2021-09-20 | GSE182528 | GEO

Expression data from MDSCs at different time points during tumor progression

Project description:Myeloid-derived suppressor cells (MDSCs) are increased by tumor-derived factors and suppress anti-tumor immunity. MDSCs obtained at a late time point after tumor injection had stronger suppressive activity than MDSCs obtained at an early time point, as measured by T cell proliferation assays. To find factors in MDSCs that change during tumor growth, we analyzed gene expression profiles from MDSCs at different time points after tumor injection. We found that immune response-related genes were down-regulated, but pro-tumor function-related genes were up-regulated in both Mo-MDSCs and PMN-MDSCs at the late time point. Among differentially expressed genes, FK506 binding protein 51 (FKBP51), which is a member of the immunophilin protein family and plays a role in immunoregulation, was increased in the Mo- and PMN-MDSCs isolated from the late time points. Experiments using siRNA and a chemical inhibitor of FKBP51 revealed that FKBP51 contributes to the regulation of the suppressive function of MDSCs by increasing iNOS, ARG1, and ROS levels and enhancing NF-kappaB activity. Collectively, our data suggest that FKBP51 is a novel molecule that can be targeted to regulate the immunosuppressive function of MDSCs. To identify the factors that licensed MDSCs to be more suppressive as tumors grow, we analyzed gene expression profiles in the two subsets of MDSCs at different time points (3wks, 6wks) during tumor progression. CD11b+Ly-6C(high)Ly-6G(low) Mo-MDSCs and CD11b+Ly-6C(low)Ly-6G(high) PMN-MDSCs were sorted from pooled spleens of naÃ¯ve mice and Her-2/CT26 tumor-bearing mice. Total RNA was purified and gene expression was analyzed by the Affymetrix GeneChipÂ® Mouse Gene 1.0 ST Array.

2012-03-29 | E-GEOD-35398 | biostudies-arrayexpress

Ablation of NLRP3 inflammasome rewires MDSC function and promotes tumor regression

Project description:Myeloid-derived suppressor cells (MDSCs) are myeloid precursors which exert potent immunosuppressive properties in cancer. Despite the extensive knowledge on mechanisms implicated in mobilization, recruitment and function of MDSCs, still their therapeutic targeting remains an unmet need in cancer immunotherapy suggesting that unappreciated mechanisms of MDSC-mediated suppression exist. Herein, we demonstrate an important role of NLRP3 inflammasome in the functional properties of MDSCs in tumor-bearing hosts. Specifically, Nlrp3-deficient mice exhibited reduced tumor growth compared to wild-type animals and induction of robust anti-tumor immunity, accompanied by re-wiring of the MDSC compartment. Interestingly, both monocytic (M-MDSCs) and granulocytic (G-MDSCs) subsets from Nlrp3-/- mice displayed impaired suppressive activity and demonstrated significant transcriptomic alterations supporting the loss-of-function and associated with metabolic re-programming. Finally, therapeutic targeting of NLRP3 inhibited tumor development and re-programmed the MDSC compartment. These findings propose that targeting NLRP3 in MDSCs could overcome tumor-induced tolerance and may provide new checkpoints of cancer immunotherapy.

2022-08-08 | GSE188973 | GEO

Exogenous Interleukin-10 versus Glucocorticoids: Effect on Gene Expression and Pro-inflammatory Cytokine Release in Polymorphonuclear Leukocytes and Monocytes of the Newborn

Project description:INTRODUCTION: Persistent lung inflammation, with an influx of polymorphonuclear leukocytes and monocytes, occurs early in bronchopulmonary dysplasia. We hypothesized that: 1) that interleukin-10, a potent anti-inflammatory cytokine, would cause a markedly different gene expression profile compared to dexamethasone in these cells, and 2) monocyte insensitivity to dexamethasone was related to glucocorticoid receptor expression. RESULTS: For polymorphonuclear leukocytes, there were <20% of genes changing expression in common between interleukin-10 and dexamethasone. The monocyte had 5 times the number of genes changing expression with interleukin-10 compared to the polymorphonuclear leukocyte. Dexamethasone, in the therapeutic range, had no effect on gene expression in monocytes. The order of potency for inhibition of interleukin-8 release from monocytes was IL-10>betamethasone>> dexamethasone and hydrocortisone. Glucocorticoid potency was directly related to the degree of glucocorticoid receptor translocation to the monocyte nucleus. DISCUSSION: Gene expression profiles by IL-10 versus dexamethasone indicates that there may be major differences in efficacy and adverse effects if interleukin-10 is used for therapy in the future. Betamethasone may be a better therapeutic choice than dexamethasone. METHODS: Isolated cord blood cells were pre-incubated with anti-inflammatory agents prior to endotoxin stimulation. Measurements were made by microarrays, RT-qPCR, ELISA, and Western blots. Isolation of cord blood polymorphonuclear leukocytes and monocytes separately from 5 subjects. Endotoxin stimulation in cell culture for 4 hours. Comparison of gene expression between endotoxin alone versus endotoxin-stimualted cells pretreated with interleukin-10 or dexamethasone (at equimolar, therapeutic levels, 10-8 M. Cell Types : MONOs, PMNs; Treatments: LPS, LPS+IL-10, LPS+DEX

2012-02-16 | E-GEOD-35683 | biostudies-arrayexpress

Lung-resident myeloid-derived suppressor cells display dual functionality in experimental tuberculosis

Project description:Using cell-based approaches and experimental mouse models for pulmonary TB we unveiled MDSCs as new myeloid populations directly interacting with Mycobacterium tuberculosis (Mtb). MDSCs readily phagocytosed Mtb, released proinflammatory (IL-6, IL-1M-NM-1) and immunomodulatory (IL-10) cytokines while retaining their suppressive capacity. MDSCs were identified at the site of infection in disease-resistant and -susceptible mice during pulmonary TB. Excessive MDSC accumulation in lungs correlated with elevated surface expression of IL-4RM-NM-1 and heightened TB lethality. Microarray experiments were performed as dual-color hybridizations on Agilent mouse whole genome catalog 44K arrays. To compensate for dye-specific effects, a dye-reversal color-swap was applied.

2014-12-21 | E-GEOD-57124 | biostudies-arrayexpress

RNA-Seq of myeloid derived suppressor cells (MDSCs) from wild-type and Rel knockout mice

Project description:Bone marrow-derived MDSCs were generated from bone marrow of naive WT or Rel-/- mice. After red blood cell lysis, BM cells were cultured in complete RPMI medium containing GM-CSF (100 ng/mL) and IL-6 (100 ng/mL) for 7 days. RNAs were collected afterwards for RNA-Seq.

2020-03-10 | E-MTAB-8674 | biostudies-arrayexpress

Expression data from cultured mouse bone-marrow monocytes.

Project description:Retinoic acid signaling regulates monocyte differentiation into dendritic cells or macrophages. We used microarrays to uncover gene expression changes associated with retinoic acid exposure in mouse monocytes. The immunosuppressive tumor microenvironment (TME) is a major barrier to immunotherapy. Within solid tumors, why monocytes preferentially differentiate into immunosuppressive tumor associated macrophages (TAMs) but not immunostimulatory dendritic cells (DCs) remains unclear. Using multiple murine sarcoma models, we found that the TME induced retinoic acid (RA) production by tumor cells, which polarized intratumoral monocyte differentiation towards TAMs and away from DCs via suppression of DC-promoting transcription factor Irf4. Genetic inhibition of RA production by tumor cells or pharmacologic inhibition of RA signaling within TME increased stimulatory monocyte-derived cells, enhanced T cell-dependent anti-tumor immunity and demonstrated striking synergy with immune checkpoint blockade. Further, RA responsive gene signature in human monocytes correlated with an immunosuppressive TME in multiple human tumors. RA has been long considered as an anti-cancer agent, but our work demonstrates its tumorigenic capability via myeloid-mediated immune suppression and provides proof of concept for targeting this pathway for tumor immunotherapy.

2020-05-01 | GSE144609 | GEO

Expression data from cultured human monocytes

Project description:Retinoic acid signaling regulates monocyte differentiation into dendritic cells or macrophages. We used microarrays to uncover gene expression changes associated with retinoic acid exposure in human monocytes. The immunosuppressive tumor microenvironment (TME) is a major barrier to immunotherapy. Within solid tumors, why monocytes preferentially differentiate into immunosuppressive tumor associated macrophages (TAMs) but not immunostimulatory dendritic cells (DCs) remains unclear. Using multiple murine sarcoma models, we found that the TME induced retinoic acid (RA) production by tumor cells, which polarized intratumoral monocyte differentiation towards TAMs and away from DCs via suppression of DC-promoting transcription factor Irf4. Genetic inhibition of RA production by tumor cells or pharmacologic inhibition of RA signaling within TME increased stimulatory monocyte-derived cells, enhanced T cell-dependent anti-tumor immunity and demonstrated striking synergy with immune checkpoint blockade. Further, RA responsive gene signature in human monocytes correlated with an immunosuppressive TME in multiple human tumors. RA has been long considered as an anti-cancer agent, but our work demonstrates its tumorigenic capability via myeloid-mediated immune suppression and provides proof of concept for targeting this pathway for tumor immunotherapy.

2020-05-01 | GSE144608 | GEO

mRNA and long noncoding RNA expression microarrays in GM-CSF or GM-CSF+IL6-induced mouse MDSC

Project description:Myeloid-derived suppressor cells (MDSCs) have emerged as major regulators of immune responses in cancer and other pathological conditions. Multiple factors including cytokines, transcription factors and multiple signaling pathways are involved in MDSC differentiation. Cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin(IL-6) etc could in vitro mediate development of MDSCs.IL-6 with GM-CSF mediated MDSC not only had stronger suppressive function but also the dynamics of their suppressive function was different from GM-CSF alone mediated MDSCs.To found a new regulatory factor (s) in tumor and inflammatory environments, we compared GM-CSF and IL-6 mediated MDSCs with GM-CSF alone mediated MDSCs using lncRNA microarray and protein-coding mRNA microarrays.

2017-10-09 | GSE104718 | GEO