RNASeq analysis of in vitro generated myeloid-derived supressor cells (MDSCs)
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE182262 | GEO | 2021/10/05
REPOSITORIES: GEO
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Project description:Myeloid-derived suppressor cells (MDSCs) as a population of myeloid cells enriched in cancer patients with immunosuppressive function. Further studies have determined that MDSCs are comprised of two groups: polymorphonuclear-MDSCs (G-MDSCs) and monocytic-MDSCs (M-MDSCs). We used a microbeads kit (Miltenyi) to isolate G-MDSCs and M-MDSCs with markers Ly6c2-Ly6g+CD11b+ and Ly6c2+Ly6g-CD11b+, respectively. And then using bulk RNA-seq to anlysis the enrichment gene expression in G-or M-MDSC which from wild type, APCmin mutant adenoma and immune deffiency mice.
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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) have the capacity to suppress T cell-mediated immune responses, and impact clinical outcome of cancer, infections and transplantation settings. Although MDSCs were initially described as bone-marrow-derived immature myeloid cells (either monocytic [m-MDSC] or granulocytic [g-MDSC]), also mature neutrophils have been shown to exert MDSC activity towards T cells, in ways that so far remained unclear. In this study, we demonstrate that human neutrophils – both from healthy donors and cancer patients – do not exert MDSC activity unless they are activated. Using neutrophils with genetically well-defined defects, we found that reactive oxygen species (ROS) and granule-derived constituents are required for MDSC activity after direct CD11b-dependent neutrophil-T cell interactions. Besides these cellular interactions, neutrophils were engaged in the uptake of pieces of T cell membrane, a process called trogocytosis. Together, these interactions led to changes in T cell morphology, mitochondrial dysfunction and ATP depletion, as indicated by electron microscopy, mass spectrometry and metabolic parameters. Our studies characterize the different steps by which activated mature neutrophils induce functional T cell non-responsiveness and irreparable cell damage.
2020-05-07 | PXD010508 | Pride
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 naïve mice and Her-2/CT26 tumor-bearing mice. Total RNA was purified and gene expression was analyzed by the Affymetrix GeneChip® Mouse Gene 1.0 ST Array.
2012-03-29 | E-GEOD-35398 | biostudies-arrayexpress
Project description:Myeloid-derived suppressor cells (MDSCs) represent a group of immature myeloid cells composed of myeloid progenitor cells and immature myeloid cells that can negatively regulate immune responses by inhibiting T cell function. Our lab and other groups have shown that injection of a lethal or sublethal dose of LPS into mice can result in the expansion of MDSCs in the bone marrow, spleen and blood. Until now, the molecular mechanisms responsible for this expansion were poorly studied. Specifically, the role of the individual microRNAs (miRNAs) involved remained largely unknown. We performed microarray analysis to compare the miRNA expression profiles of Gr-1+CD11b+ cells sorted from the bone marrow of LPS-injected and PBS-injected mice. We identified let-7e, which was highly upregulated in the LPS-treated group, as a potent regulator of LPS-induced MDSC expansion. Furthermore, let-7e overexpression in bone marrow chimeric mice leads to a noticeable increase in the population of Gr-1+CD11b+ cells, which results from reduced cellular apoptosis. Further studies showed that let-7e can directly target caspase-3 to inhibit cell apoptosis, and upregulation of let-7e in LPS-stimulated MDSCs could be due to the relieved repression of let-7e transcription exerted by downregulated GATA2. Our findings suggest that LPS expands MDSCs by inhibiting apoptosis through the regulation of the GATA2/let-7e axis.
2018-08-11 | GSE118398 | 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:Does the adoptive transfer of MDSCs modulate lymphocyte (T cell) functions? Microarray expression analysis of T cells from MDSC-treated mice after Blunt chest trauma (TxT)
2022-06-16 | GSE188171 | GEO
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) 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:Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that accumulate in the tumor microenvironment (TME). MDSCs have been shown to dampen anti-tumor immune responses and promote tumor growth; however, the mechanisms of MDSC induction and their role in promoting immune suppression in cancer remain poorly understood. Here, we characterized the phenotype and function of monocytic MDSCs (M-MDSCs) generated by co-culture of human peripheral blood mononuclear cells with SK-MEL-5 cancer cells in vitro. We selected the SK-MEL-5 human melanoma cell line to generate M-MDSCs because these cells form subcutaneous tumors rich in myeloid cells in humanized mice. M-MDSCs generated via SK-MEL-5 co-culture expressed low levels of human leukocyte antigen (HLA)-DR, high levels of CD33 and CD11b and suppressed both CD8+ T cell proliferation and IFN-γ secretion. M-MDSCs also expressed higher levels of immunoglobulin-like transcript 3 (ILT3, also known as LILRB4) and immunoglobulin-like transcript 4 (ILT4, also known as LILRB2) on the cell surface compared to monocytes. We, therefore, investigated how ILT3 targeting could modulate M-MDSC cell function. Treatment with an anti-ILT3 antibody impaired the acquisition of the M-MDSC suppressor phenotype and reduced the capacity of M-MDSCs to cause T cell suppression. Finally, in combination with anti-programmed cell death protein 1 (PD1), ILT3 blockade enhanced T cell activation as assessed by IFN-γ secretion. These results suggest that ILT3 expressed on M-MDSCs has a role in inducing immunosuppression in cancer and that antagonism of ILT3 may be useful to reverse the immunosuppressive function of M-MDSCs and enhance the efficacy of immune checkpoint inhibitors.
2021-01-29 | GSE160401 | GEO