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Tumor-infiltrating Monocytic Myeloid-derived suppressor cells play a key role in forming immunosuppressive microenvironment in human gastric cancer

ABSTRACT: The present data suggest that M-MDSC, play a predominant role in forming the immunosuppressive microenvironment in GC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE231539 | GEO | 2024/01/22

REPOSITORIES: GEO

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Tumor-infiltrating monocytic myeloid-derived suppressor cells contribute to the development of an immunosuppressive tumor microenvironment in gastric cancer

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Tumor-infiltrating Monocytic Myeloid-derived suppressor cells play a key role in forming immunosuppressive microenvironment in human gastric cancer

Project description:Tumor-infiltrating Monocytic Myeloid-derived suppressor cells play a key role in forming immunosuppressive microenvironment in human gastric cancer

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Tumor-infiltrating monocytic myeloid-derived suppressor cells contribute to the development of an immunosuppressive tumor microenvironment in gastric cancer

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ILT3 (LILRB4) Promotes the Immunosuppressive Function of Tumor-Educated Human Monocytic Myeloid-Derived Suppressor Cells

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.

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Tumor-infiltrating monocytic myeloid-derived suppressor cells mediate CCR5-dependent recruitment of regulatory T cells favoring tumor growth

Project description:Analysis of MDSC subsets from naive blood and RMA-S blood and RMA-S tumor, respectively. Tumor-infiltrating MO-MDSCs changed their expression pattern compared to blood and exhibited high levels of chemokines Total RNA obtained from PMN-MDSCs and MO-MDSCs from naive blood or from blood and tumor of RMA-S bearing mice

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Project description:Myeloid-derived suppressor cells (MDSCs) are a group of heterogeneous cells derived from immature myeloid cells (IMCs). MDSCs are known to play important roles in tumor immune evasion. While we know that there are a large number of circulating and tumor-infiltrating MDSCs existing in gastric cancer (GC) patients, the phenotypic characteristics and arginase 1 (ARG1) expression levels of these MDSCs remain very unclear. In our study, flow cytometric analysis of circulating MDSCs from 20 gastric adenocarcinoma (GAC) patients found that ≥80% ARG1-expressing MDSCs were mainly early-stage MDSCs (HLA-DR-CD33+CD14-CD15-MDSCs). In addition, our investigation showed that tumor-infiltrating MDSCs from 6 GAC patients consisted of >35% ARG1-expressing naïve MDSCs (HLA-DR-CD33-CD11b-CD14-CD15-MDSCs), >15% early-stage MDSCs and >40% monocytic MDSCs (HLA-DR-CD14+MDSCs). This preliminary study describes the phenotypic characteristics and ARG1 expression levels of MDSCs from GAC patients and shows that circulating and tumor-infiltrating ARG1-expressing cells were mainly immature and monocytic MDSCs, which provides information to better understand the mechanisms that allow gastric cancer cells to evade the immune system.

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Monocytic myeloid-derived suppressor cells accumulate in the lungs of influenza A virus-infected mice

Project description:Influenza A virus (IAV) infection causes an acute respiratory disease characterized by a strong inflammatory immune response and severe immunopathology. Pro-inflammatory mechanisms are well described in the murine IAV infection model, but less is known about the mechanisms leading to the resolution of inflammation. Here, we analyzed the contribution of monocytic myeloid-derived suppressor cells (mono-MDSC) to this process. An accumulation of mono-MDSC within the lungs was observed during the course of IAV infection and phenotypic characterization of these mono-MDSC by flow cytometry and RNA-Seq revealed an activated phenotype showing both pro- and anti-inflammatory features, including the expression of iNOS by a fraction of cells in an IFN-g-dependent manner. Mono-MDSC isolated from lungs of IAV-infected animals displayed suppressive activity when tested in vitro, and iNOS inhibitors could abrogate this suppressive activity. Collectively, our data suggest that during IAV infection monocytes can differentiate into mono-MDSC, which might contribute to the prevention of immunopathology during this life-threatening disease.

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Modified method for differentiation of myeloid-derived suppressor cells in vitro enhances immunosuppressive ability via glutathione metabolism

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.

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