KIRA6 abrogates the generation of myeloid-derived suppressor cells and overcomes resistance to anti-PD-1 therapy
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE304255 | GEO | 2025/08/06
REPOSITORIES: GEO
Similar Datasets
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) 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.
2021-11-03 | PXD023337 | Pride
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.
2021-01-01 | GSE163399 | 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:This study presents an integrative analysis identifying a 26-gene signature associated with myeloid-derived suppressor cells (MDSCs) in cancer, leveraging mass spectrometry proteomics data, RNA sequencing data and external datasets from lung and head and neck cancers. The genes within this signature were found to correlate positively with MDSC infiltration and negatively with neutrophil and CD8+ T cell presence in the tumor microenvironment. Clinically, this signature showed a significant association with reduced survival rates in metastatic melanoma patients treated with PD1 inhibitors, highlighting its potential as a prognostic biomarker in cancer therapy. This study enhances our understanding of MDSCs in oncology and opens new avenues for targeted therapeutic strategies against MDSC-mediated immunosuppression in the tumor microenvironment.
2024-06-22 | PXD048934 | Pride
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 (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:Chronic inflammation and immunosuppressive microenvironment promote prostate cancer (PCa) metastasis and diminish the responses to immune checkpoint blockade (ICB) therapies. However, it remains unclear how and to what extent these two events are coordinated. Here we show that ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, functions downstream of inflammation induced IKKb activation to shape immunosuppressive tumor microenvironment (TME). Prostate-specific deletion of Arid1a cooperates with Pten loss to produce a metastasis-prone tumors. We identify that polymorphonuclear myeloid-derived suppressor cells (MDSCs) as the major infiltrating immune cell type to cause immune evasion, and neutralization of MDSCs restricts metastasis of Arid1a deficient tumors. Mechanistically, inflammation cues activate IKKβ to phosphorylate ARID1A, leading to its degradation via b-TRCP. ARID1A downregulation in turn silences the enhancer of A20 deubiquitinase, a critical negative regulator of NF-kB signaling, and thereby unleashing CXCR2 ligands-mediated MDSC chemotaxis. Importantly, our results support the therapeutic strategy of anti-NF-kB or CXCR2 combined with ICB for advanced PCa. Together, our findings highlight a critical role of ARID1A in MDSCs recruitment and demonstrate IKKb/ARID1A/NF-kB feedback axis integrating inflammation and the immunosuppression to drive PCa metastasis.
2022-11-07 | GSE213251 | GEO
Project description:Chronic inflammation and immunosuppressive microenvironment promote prostate cancer (PCa) metastasis and diminish the responses to immune checkpoint blockade (ICB) therapies. However, it remains unclear how and to what extent these two events are coordinated. Here we show that ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, functions downstream of inflammation induced IKKb activation to shape immunosuppressive tumor microenvironment (TME). Prostate-specific deletion of Arid1a cooperates with Pten loss to produce a metastasis-prone tumors. We identify that polymorphonuclear myeloid-derived suppressor cells (MDSCs) as the major infiltrating immune cell type to cause immune evasion, and neutralization of MDSCs restricts metastasis of Arid1a deficient tumors. Mechanistically, inflammation cues activate IKKβ to phosphorylate ARID1A, leading to its degradation via b-TRCP. ARID1A downregulation in turn silences the enhancer of A20 deubiquitinase, a critical negative regulator of NF-kB signaling, and thereby unleashing CXCR2 ligands-mediated MDSC chemotaxis. Importantly, our results support the therapeutic strategy of anti-NF-kB or CXCR2 combined with ICB for advanced PCa. Together, our findings highlight a critical role of ARID1A in MDSCs recruitment and demonstrate IKKb/ARID1A/NF-kB feedback axis integrating inflammation and the immunosuppression to drive PCa metastasis.
2022-11-07 | GSE197687 | GEO
Project description:Chronic inflammation and immunosuppressive microenvironment promote prostate cancer (PCa) metastasis and diminish the responses to immune checkpoint blockade (ICB) therapies. However, it remains unclear how and to what extent these two events are coordinated. Here we show that ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, functions downstream of inflammation induced IKKb activation to shape immunosuppressive tumor microenvironment (TME). Prostate-specific deletion of Arid1a cooperates with Pten loss to produce a metastasis-prone tumors. We identify that polymorphonuclear myeloid-derived suppressor cells (MDSCs) as the major infiltrating immune cell type to cause immune evasion, and neutralization of MDSCs restricts metastasis of Arid1a deficient tumors. Mechanistically, inflammation cues activate IKKβ to phosphorylate ARID1A, leading to its degradation via b-TRCP. ARID1A downregulation in turn silences the enhancer of A20 deubiquitinase, a critical negative regulator of NF-kB signaling, and thereby unleashing CXCR2 ligands-mediated MDSC chemotaxis. Importantly, our results support the therapeutic strategy of anti-NF-kB or CXCR2 combined with ICB for advanced PCa. Together, our findings highlight a critical role of ARID1A in MDSCs recruitment and demonstrate IKKb/ARID1A/NF-kB feedback axis integrating inflammation and the immunosuppression to drive PCa metastasis.
2022-11-07 | GSE197686 | GEO