Suppressive function of MDSC is under bidirectional control of intrinsic and immunotherapy-induced type I IFN in pancreatic cancer
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE126879 | GEO | 2019/11/19
REPOSITORIES: GEO
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Project description:Myeloid derived suppressor cells (MDSC) playing the immune suppressive roles in tumor bearing host consists of two major subsets of granulocytic and monocytic cells. Granulocytic MDSC (G-MDSC) express CD11b+ Gr-1high Ly6G+ Ly6Clow and produce high level of reactive oxygen species (ROS). Interestingly, neutrophils are well known ROS producing cells during immune defensive process and share same surface markers with G-MDSC. These similar features always brought the fundamental questions what’s the difference between G-MDSC and neutrophils but it’s not yet proven clearly. In this study, we examined the gene expression of G-MDSC and neutrophils using Affymetrix microarray G-MDSC (CD11b+Ly6G+Ly6Clow) were purifed from splenocytes in EL4 lymphoma tumor bearing mice by positive selection of Ly6G using microbeads isolation. Neutrophils were purified from ascitic fluids induced after injection of milk protein, casein by negative selection of F4/80 and positive selection of Ly6G using microbeads isolation. Their RNA was extracted and gene expression was analyzed using Affymetrix microarray.
2011-03-10 | E-GEOD-24102 | biostudies-arrayexpress
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
Project description:Myeloid derived suppressor cells (MDSC) playing the immune suppressive roles in tumor bearing host consists of two major subsets of granulocytic and monocytic cells. Granulocytic MDSC (G-MDSC) express CD11b+ Gr-1high Ly6G+ Ly6Clow and produce high level of reactive oxygen species (ROS). Interestingly, neutrophils are well known ROS producing cells during immune defensive process and share same surface markers with G-MDSC. These similar features always brought the fundamental questions what’s the difference between G-MDSC and neutrophils but it’s not yet proven clearly. In this study, we examined the gene expression of G-MDSC and neutrophils using Affymetrix microarray
2011-03-10 | GSE24102 | GEO
Project description:Myeloid-derived suppressor cells (MDSC) include immature monocytic (M-MDSC) and granulocytic (PMN-MDSC) cells that share the ability to suppress adaptive immunity and hinder the effectiveness of anti-cancer treatments. Of note, in response to interferon-γ (IFNγ) M-MDSC release the tumor-promoting and immunosuppressive molecule nitric oxide (NO), whereas macrophages largely express anti-tumor properties. Investigating these opposing activities, we found that tumor-derived prostaglandin E2 (PGE2) induces nuclear accumulation of p50 NF-κB in M-MDSC, diverting their response to IFNγ towards NO-mediated immunosuppression and reducing TNFα expression. At the genome level, p50 NF-κB promoted binding of STAT1 to regulatory regions of selected IFNγ-dependent genes, including inducible nitric oxide synthase (Nos2). In agreement, ablation of p50 as well as pharmacological inhibition of either the PGE2 receptor EP2 or NO production reprogrammed M-MDSC towards a NOS2low/TNFαhigh phenotype, restoring the in vivo antitumor activity of IFNγ. Our results indicate that inhibition of the PGE2/p50/NO axis prevents MDSC suppressive functions and restores the efficacy of anticancer immunotherapy.
2020-05-15 | GSE84468 | GEO
Project description:Tumor growth is associated with a profound alteration of myelopoiesis, leading to recruitment of immunosuppressive cells known as myeloid-derived suppressor cells (MDSCs). Analyzing the cytokines affecting myelo-monocytic differentiation produced by various experimental tumors, we found that GM-CSF, G-CSF, and IL-6 allowed a rapid generation of MDSCs from precursors present in mouse and human bone marrow (BM). BM-MDSCs induced by GM-CSF+IL-6 possessed the highest tolerogenic activity, as revealed by the ability to impair the priming of IFN- -producing CD8+ T cells upon in vivo adoptive transfer. Moreover, adoptive transfer of syngeneic, GM-CSF+IL-6-conditioned MDSCs to diabetic mice transplanted with allogeneic pancreatic islets resulted in long term acceptance of the allograft and correction of the diabetic status. Cytokines inducing MDSCs acted on a common molecular pathway. Immunoregulatory activity of both tumor-induced and BM-derived MDSCs was entirely dependent on C/EBP transcription factor, a key component of the emergency myelopoiesis triggered by stress and inflammation. Adoptive transfer of tumor antigen-specific CD8+ T lymphocytes resulted in therapy of established tumors only in mice lacking C/EBP in myeloid compartment. These data unveil another link between inflammation and cancer and identify a novel molecular target to control tumor-induced immune suppression. We used gene expression analysis to identify those factors, secreted by tumor-infiltrating MDSC, which could drive emathopoiesis. Moreover we compare gene expression profile of tumor-induced MDSC, obtained from either the spleen and the tumor infiltrate of tumor bearing mice, and in vitro bone marrow-derived MDSC. CD11b+ cells were immunomagnetically enriched from various murine tissue and experimental conditions, and cRNA samples were prepared accordingly to Expression Analysis: Technical Manual. 701021 Rev. 5. Santa Clara, CA, Affymetrix; 2004, and hybridized to the Affymetrix GeneChip MOE430 2.0 array which contains more than 45,000 probe sets, representing more than 34,000 genes. CD11b+ cells obtained from the spleen of healthy BALB/c and C57BL/6 mice were used as reference sample for tumor induced CD11b+ MDSC, enriched from either the spleen and the tumor infiltrate of tumor-bearing mice. Moreover CD11b+ cells enriched from fresh bone marrow were used as reference sample for in vitro bone marrow-differentiated MDSC, obtained with either GM-CSF+IL-6 and GM-CSF+G-CSF 4 days cytokine cocktail treatment.
2010-06-16 | E-GEOD-21927 | biostudies-arrayexpress
Project description:Myeloid derived Suppressor cells (MDSC) are heterogenous popluation of cells consists of two major subsets namely the monocytic Gr-1dull/int. and granulocytic (Gr-1high). These distinct two subsets use different mechanism to inhibit T cell response. In addition, how the function of these subsets is regulated is not known yet. The Gr-1dull/int. MDSC are suppressing T cells through IFNg dependent nitric oxide dependent manner. However, the exact suppressive mechanism of Gr-1high MDSC is not clear. Here we studied the role of a cytokine IFNg on the suppressive function of Gr-1high MDSC by comparing the gene expression of Gr-1high cells cultured alone versus those cultured with T cells which donot produce IFNgamma. CD11b+Gr-1high cells were purified from the splenocyte of CT-26 colon tumor bearing mice. The purified CD11b+Gr-1high MDSCs were cultured with IFNg-/- antigen specific T cells and re- sorted after 48h and RNA was extracted and gene expression was analyzed using topic-defined PIQORTM Immunology Microarrays.
2011-09-08 | E-GEOD-32000 | biostudies-arrayexpress
Project description:CD11b+ myeloid-derived suppressor cells (MDSCs) have been shown to become activated at the tumor site and acquired a more suppressive phenotype compared to the splenic counterpart. This activated status promotes cancer progression by creating an immune suppressive niche around the tumor, by providing nourishment to the neoplastic cells, and by promoting metastases. To start understanding the differences between splenic and tumor infiltrating CD11b, genome-wide transcriptome analysis was performed. We used gene expression analysis to identify those factors, secreted by tumor-infiltrating MDSC, which could drive emathopoiesis. Moreover, we compare gene expression profile of tumor-induced MDSC, obtained from either the spleen or the tumor infiltrate of tumor-bearing mice.
2020-06-21 | GSE110772 | GEO
Project description:Myeloid derived suppressor cells (MDSC) are critical in regulating immune responses by suppressing antigen presenting cells (APC) and T cells. We previously observed that incubation of peripheral blood monocytes with IL-10 during their differentiation to dendritic cells (moDC) results in the generation of an APC population with a CD14+HLA-DRlow phenotype (IL-10-APC) with reduced stimulatory capacity similar to human MDSC. Here, we show that co-incubation of IL-10-APC and moDC caused a reduction of DC-induced T cell proliferation, of the expression of maturation markers and of secreted cytokines and chemokines. Furthermore, addition of IL-10-APC increased the immunosuppressive molecule osteoactivin and its corresponding receptor syndecan-4 on moDC. Using transcriptome analysis, we could identify a set of molecules and pathways mediating the immunosuppressive effects of IL-10-APCs. In addition, we found that IL-10-APC as well as human isolated MDSC, expressed higher levels of programmed death (PD)-1, PD-ligand-1, glucocorticoid-induced-tumor-necrosis-factor-receptor-related-protein (GITR) and GITR-ligand. Inhibition of osteoactivin, syndecan-4, PD-1 or PD-L1 on MDSC using blocking antibodies restored the stimulatory capacity of DC in co-incubation experiments. Our results demonstrate that osteoactivin/syndecan-4 and PD-/PD-L1 are key molecules that are profoundly involved in the inhibitory effects of MDSC on DC function and might be promising tools for an application in the clinics.
2017-04-03 | GSE92852 | GEO
Project description:Myeloid-derived suppressor cells (MDSC) represent a heterogeneous population of immature myeloid cells that accumulate in blood, liver, spleen and tumors upon chronic inflammation and tumor development in patients and mice. Acute hepatitis is characterized by a fast infiltration of inflammatory cells in the liver and increased enzymatic activity at this organ that could lead into liver fibrosis and cirrhosis. We have studied the biology of hepatic MDSC in acute hepatitis. Unexpectedly, hepatic MDSC, which accumulate in the liver of mice bearing subcutaneous tumors, failed to suppress inflammatory responses upon Con A injection, but instead were responsible for exacerbating acute liver damage. Phenotypic, genetic and functional studies demonstrated rapid changes of hepatic MDSC from a suppressor phenotype into a pro-inflammatory subset as early as 3 hours after Con A injection. An increase in the expression of pro-inflammatory cytokines, costimulatory molecules such as CD80, CD86 and CD40 along with a loss of suppressor function was noticed in mice upon Con A treatment. These changes were CD40-dependent and not found in CD40-/- MDSC. Interestingly, CD40 ligation of human MDSC in vitro resulted in down-regulation of arginase I expression and suppressor function. Finally, blockade of ROS production in hepatic MDSC ameliorated hepatocyte damage suggesting that MDSC mediated toxicity was ROS dependent. We believe that these findings reflect how MDSC plasticity can be modulated to promote inflammation, opening a new path for therapies targeting innate suppressive cells in cancer patients. EL4 tumors were established in C57BL/6 mice, then mice were injected either with PBS (n=3) or 12.5mg/kg Con A (n=3). Three hours later mice were sacrificed, liver CD11b+Gr-1+ cells were sorted and samples were processed for gene expression analysis.
2015-09-01 | E-GEOD-50949 | biostudies-arrayexpress
Project description:Myeloid-derived suppressor cells (MDSC) is a heterogeneous population of cells that can negatively regulate T-cell function. As opposed to murine MDSC, which are characterized as Gr-1+CD11b+ cells, human MDSC are not so clearly defined due to lack of specific markers. Our lab has previously identified a new subset of MDSC as CD14+HLA-DR-neg/low cells from PBMC. CD14+HLA-DR-neg/low MDSC not only suppress proliferation and IFN-gamma secretion of autologous T cells, but also induce CD25+Foxp3+ regulatory T cells that are suppressive in vitro, whereas the counterpart CD14+HLA-DR-high monocytes don’t have the effect. In this study, we compare the immune-related gene expression between CD14+HLA-DR-neg/low MDSC and CD14+HLA-DR-high monocytes to better characterize the difference between these two populations and to find new potential specific marker for human MDSC. PBMC were isolated from fresh blood healthy donor by density centrifugation. CD14+ cells were isolated by AutoMACS CD14 microbeads using a AutoMACS (Miltenyi), and then stained with CD14 and HLA-DR antibodies. MDSC and monocytes control cells were sorted as CD14+ HLA-DR-neg/low and CD14+HLA-DR-high cells respectively. The sorted two populations were immediately frozen in liquid nitrogen and shipped to the company on dry ice for RNA isolation and further microarray.
2011-09-08 | E-GEOD-32001 | biostudies-arrayexpress