Ablation of NLRP3 inflammasome rewires MDSC function and promotes tumor regression
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE188973 | GEO | 2022/08/08
REPOSITORIES: GEO
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Project description:Alterations in myelopoiesis are common across various tumor types, resulting in immature populations termed myeloid-derived suppressor cells (MDSCs). MDSC burden correlates with poorer clinical outcomes, credited to their ability to suppress antitumor immunity. MDSCs consist of two major subsets, monocytic and polymorphonuclear (PMN). Intriguingly, the latter subset predominates in many patients and tumor models, though the mechanisms favoring PMN-MDSC responses remain poorly understood. Ordinarily, lineage-restricted transcription factors regulate myelopoiesis that collectively dictate cell fate. One integral player is interferon regulatory factor-8 (IRF8), which promotes monocyte/dendritic cell differentiation while limiting granulocyte development. We recently showed that IRF8 inversely controls MDSC burden in tumor models, particularly the PMN-MDSC subset. However, where IRF8 acts in the pathway of myeloid differentiation to influence PMN-MDSC production has remained unknown. Here, we showed that: 1) tumor growth was strongly associated with a selective expansion of newly defined IRF8lo granulocytic progenitors (GPs); 2) tumor-derived GPs had an increased ability to form PMN-MDSCs; 3) tumor-derived GPs shared gene expression patterns with IRF8-/- GPs, suggesting that IRF8 loss underlies GP expansion; and 4) enforced IRF8 overexpression in vivo selectively constrained tumor-induced GP expansion. These findings support the hypothesis that PMN-MDSCs result from selective expansion of IRF8lo GPs, and that strategies targeting IRF8 expression may limit their load to improve immunotherapy efficacy.
2022-08-31 | GSE193263 | GEO
Project description:Alterations in myelopoiesis are common across various tumor types, resulting in immature populations termed myeloid-derived suppressor cells (MDSCs). MDSC burden correlates with poorer clinical outcomes, credited to their ability to suppress antitumor immunity. MDSCs consist of two major subsets, monocytic and polymorphonuclear (PMN). Intriguingly, the latter subset predominates in many patients and tumor models, though the mechanisms favoring PMN-MDSC responses remain poorly understood. Ordinarily, lineage-restricted transcription factors regulate myelopoiesis that collectively dictate cell fate. One integral player is interferon regulatory factor-8 (IRF8), which promotes monocyte/dendritic cell differentiation while limiting granulocyte development. We recently showed that IRF8 inversely controls MDSC burden in tumor models, particularly the PMN-MDSC subset. However, where IRF8 acts in the pathway of myeloid differentiation to influence PMN-MDSC production has remained unknown. Here, we showed that: 1) tumor growth was strongly associated with a selective expansion of newly defined IRF8lo granulocytic progenitors (GPs); 2) tumor-derived GPs had an increased ability to form PMN-MDSCs; 3) tumor-derived GPs shared gene expression patterns with IRF8-/- GPs, suggesting that IRF8 loss underlies GP expansion; and 4) enforced IRF8 overexpression in vivo selectively constrained tumor-induced GP expansion. These findings support the hypothesis that PMN-MDSCs result from selective expansion of IRF8lo GPs, and that strategies targeting IRF8 expression may limit their load to improve immunotherapy efficacy.
2017-04-06 | GSE87800 | GEO
Project description:Myeloid Derived Suppressor Cells (MDSCs) promote immunosuppressive activities in the tumor microenvironment (TME), resulting in increased tumor burden and diminishing the anti-tumor response of immunotherapies. While primary and metastatic tumors are typically the focal points of therapeutic development, the immune cells of the TME are uniquely programmed by the tissue of the metastatic site. In particular, MDSCs are programmed uniquely within different organs in the context of tumor progression. Given that MDSC plasticity is shaped by the surrounding environment, the proteome of MDSCs from different metastatic sites are hypothesized to be unique. A bottom-up proteomics approach using Sequential Window Acquisition of All Theoretical Mass Spectra (SWATH-MS) was used to quantify the proteome of CD11b+ cells derived from murine liver metastases (LM) and lung metastases (LuM). A comparative proteomics workflow was employed to compare MDSC proteins from LuM (LuM-MDSC) and LM (LM-MDSC) while also elucidating common signaling pathways, protein function, and possible drug-protein interactions.
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Project description:Myeloid-derived suppressor cells (MDSCs) are immune suppressive cells that massively accumulate under pathological conditions to suppress T cell immune response. Dysregulated cell death contributes to MDSC accumulation, but the molecular mechanism underlying this cell death dysregulation is not fully understood. We report here that neutral ceramidase (N-acylsphingosine amidohydrolase, ASAH2) is highly expressed in tumor-infiltrating MDSCs in colon carcinoma and acts as a MDSC survival factor. To target ASAH2, we performed molecular docking based on human ASAH2 protein structure. Enzymatic inhibition analysis of identified hits determined NC06 as an ASAH2 inhibitor. Chemical and NMR analysis determined NC06 as 7-chloro-2-(3-chloroanilino)pyrano[3,4-e][1,3]oxazine-4,5-dione. NC06 inhibits ceramidase activity with IC50 of 10.16-25.91 M for human ASAH2 and 18.6-30.2 uM for mouse Asah2 proteins. NC06 induces MDSC death in a dose-dependent manner and inhibition of ferroptosis decreased NC06-induced MDSC death. NC06 increases glutathione synthesis and decrease lipid ROS to suppress ferroptosis in MDSCs. Gene expression profiling identified p53 pathway as the Asah2 target in MDSCs. Inhibition of Asah2 increased p53 protein stability to up-regulate Hmox1 expression to suppress lipid ROS production to suppress ferroptosis in MDSCs. NC06 therapy increases MDSC death and reduces MDSC accumulation in tumor-bearing mice, resulting in increased activation of tumor-infiltrating CTLs and suppression of tumor growth in vivo. Our data indicate that ASAH2 protects MDSCs from ferroptosis through destabilizing p53 protein to suppress the p53 pathway in MDSCs in the tumor microenvironment. Targeting ASAH2 with NC06 to induce MDSC ferroptosis is potentially an effective therapy to suppress MDSC accumulation in cancer immunotherapy.
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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 known to contribute to immune evasion in cancer. However, the function of the human granulocytic (G)-MDSC subset during tumor progression is largely unknown, and there are no established markers for their identification in human tumor specimens. Using gene expression profiling, mass cytometry and tumor microarrays, we here demonstrate that human G-MDSCs occur as neutrophils at distinct maturation stages, with a disease-specific profile. G-MDSCs derived from patients with metastatic breast cancer (MBC) and malignant melanoma display a unique immature neutrophil profile, that is more similar to healthy donor neutrophils than to G-MDSCs from sepsis patients. Finally, we show that primary G-MDSCs from MBC patients co-transplanted with breast cancer cells, promote tumor growth and affect vessel formation, leading to myeloid immune cell exclusion. Our findings reveal a role for human G-MDSC in tumor progression and have clinical implications also for targeted immunotherapy.
2020-09-19 | GSE157737 | GEO
Project description:Myeloid-derived suppressor cells (MDSCs), which accumulate in tumor bearers, are known to suppress anti-tumor immunity and thus promote tumor progression. MDSCs are considered a major cause of resistance against immune checkpoint inhibitors in patients with cancer. Therefore, MDSCs are potential targets in cancer immunotherapy. In this study, we modified an in vitro method of MDSC differentiation. Upon stimulating bone marrow (BM) cells with granulocyte-macrophage colony-stimulating factor in vitro, we obtained both lymphocyte antigen 6G positive (Ly-6G+) and negative (Ly-6G−) MDSCs (collectively, hereafter referred to as conventional MDSCs), which were non-immunosuppressive and immunosuppressive, respectively. We then found that MDSCs differentiated from Ly-6G− BM (hereafter called 6G− BM-MDSC) suppressed T-cell proliferation more strongly than conventional MDSCs, whereas the cells differentiated from Ly-6G+ BM (hereafter called 6G+ BM-MDSC) were non-immunosuppressive. In line with this, conventional MDSCs or 6G− BM-MDSC, but not 6G+ BM-MDSC, promoted tumor progression in tumor-bearing mice. Moreover, we identified that activated glutathione metabolism was responsible for the enhanced immunosuppressive ability of 6G− BM-MDSC. Finally, we showed that Ly-6G+ cells in 6G− BM-MDSC, which exhibited weak immunosuppression, expressed higher levels of Cybb mRNA, an immunosuppressive gene of MDSCs, than 6G+ BM-MDSC. Together, these data suggest that the depletion of Ly-6G+ cells from the BM cells leads to differentiation of immunosuppressive Ly-6G+ MDSCs. In summary, we propose a better method for MDSC differentiation in vitro. Moreover, our findings contribute to the understanding of MDSC subpopulations and provide a basis for further research on MDSCs.
2023-01-10 | GSE218704 | GEO
Project description:Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that accumulate in the tumor microenvironment of most cancer patients. There MDSCs suppress both adaptive and innate immune responses, hindering immunotherapies. Moreover, many cancers are accompanied by inflammation, a processes that further intensifies MDSC suppressive activity, causing aggressive tumor progression and metastasis. MDSCs collected from tumor-bearing mice profusely release nano-scale membrane-bound extracellular vesicles, called exosomes, which carry biologically active proteins between cells and contribute directly to the immune suppressive functions of MDSC. Many studies on other cell types have shown that exosomes may also carry microRNAs (miRNAs) and messenger RNAs (mRNAs) which can also be transferred to surrounding and distant cells. However, to the best of our knowledge, the miRNA and mRNA cargo of MDSC-derived exosomes has not yet been interrogated. This study aims to identify and quantify the cargo of MDSC and their immunosuppressive exosomes to gather knowledge that can offer insights on the mechanisms by which MDSCs contribute to immune suppression, focusing on the role of exosomes as intercellular communication mediators in the tumor microenvironment. In order to achieve our objective a well-established mouse model based on a conventional mammary carcinoma (4T1 cells) and heightened inflammation (4T1 transduced to express the cytokine interleukin-1b) was used. We provide evidence that MDSC-derived exosomes carry proteins, mRNAs and miRNAs. Relative quantitation demonstrated quantitative differences between the exosome cargo and the cargo of their parental cells, supporting the hypothesis that selective loading into the exosomes is possible. Additionally, quantitative and functional analyses of the exosome cargo generated under conventional and heightened inflammation conditions are consistent with clinical observations that inflammation is linked to cancer development.
2017-11-17 | PXD006204 | Pride
Project description:Massive accumulation of myeloid-derived suppressor cells (MDSCs) is a hallmark of cancer. It is well-known that proinflammatory mediators induce MDSC accumulation. However, the functions of cell death pathways in MDSC survival and the mechanism underlying regulation of cell death pathways in MDSCs are still elusive. Herein, we determined that DNA methylation sustains MDSC accumulation in tumor-bearing mice since pharmacological inhibition of DNMTs with Dacitabine abolished MDSC accumulation and activated antigen-specific cytotoxic T lymphocytes in tumor-bearing mice. Decreased MDSC accumulation is correlated with increased IRF8 expression in MDSCs. However, Dacitabine also abolished CD11b+Gr1+ MDSC-like cell accumulation in IRF8 KO mice, suggesting that DNA methylation regulates MDSC accumulation at the post lineage differentiation stage. Use of cell death pathway-selective inhibitors identified necroptosis as the target of DNA methylation in MDSCs. Genome-wide DNA bisulfite sequencing revealed that the promoter of Tnf is hypermethylated in tumor-induced MDSCs. Consequently, decitabine dramatically increased TNF level in MDSCs and neutralizing TNF significantly decreased Dacitabine-induced MDSC cell death. Recombinant TNF induced MDSC cell cells in a dose and RIP1-dependent manner. Inhibition of RIP1 or RIP3 did not decrease TNF expression in MDSCs. Our data determined that the TNF-RIP1 necroptosis pathway is responsible at least in part for MDSC accumulation and that the IL6-activated DNMTs hypermethylate Tnf to impair necroptosis pathway to maintain MDSC accumulation in cancer. Our data depict the IL6-STAT3-DNMT-TNFa-RIP1 necroptosis pathway as a molecular target for suppressing MDSC accumulation in cancer immunotherapy.
2020-08-01 | GSE144649 | GEO
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