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

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

PROVIDER: PRJNA673165 | ENA |

REPOSITORIES: ENA

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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.

2021-01-29 | GSE160401 | GEO

Myeloid-derived Suppressor Cells in Colorectal Cancer

Project description:The aim of the study is to evaluate whether the preoperative level of myeloid-derived suppressor cells is associated with postoperative complications classified by Clavien-Dindo categories. Levels of all MDSC, polymorphonuclear MDSC (PMNMDSC), monocytic MDSC (MMDSC), early-stage MDSC (EMDSC) and monocytic to polymorphonuclear MDSC ratio (M/PMN MDCS) were established and compared in patients with postoperative complications, severe postoperative complications (>= IIIA according to Clavien-Dindo) and severe septic complications.

| 2381881 | ecrin-mdr-crc

Autophagic monocytic myeloid-derived suppressor cells protect mice cardiac allografts

Project description:Autophagic monocytic myeloid-derived suppressor cells protect mice cardiac allografts

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Transcriptome analysis of p16/p21-dependent monocytic myeloid-derived suppressor cells accumulation.

Project description:p16 and p21 act as tumor suppressors through induction of cellular senescence. However, senescence-independent roles of these CDK inhibitors are not known. To identify the mechanism responsible for the failure of Mo-MDSCs (monocytic myeloid-derived suppressor cells) infiltration into tumor allografts in p16/p21-double knockout (DKO) mice, we searched for chemokine receptors that were highly expressed in Mo- but not PMN-MDSCs (polymorphonuclear myeloid-derived suppressor cells) and were downregulated in p16/p21-DKO as compared to WT Mo-MDSCs. Ccr2, Ccr5, and Cx3cr1 were identified by RNA-seq analysis.

2018-02-13 | GSE93359 | GEO

Autophagic monocytic myeloid-derived suppressor cells protect mice cardiac allografts

Project description:Background: Myeloid-derived suppressor cells (MDSCs) could prevent allograft rejections and induce immune tolerance in transplantation models. Previous studies demonstrated that inhibition of mTOR signal could enhance MDSCs protective effect in cardiac transplantation model via promoting MDSCs expansion. And the inhibition of mTOR is related with autophagy. Herein, this study was designed to investigate the protective mechanism of mTOR deficiency M-MDSCs in cardiac transplantation model. Methods: Myeloid-specific mTOR conditional knockout mice were generated to get mTOR deficiency M-MDSCs. The proliferation and immunosuppressive function of mTOR deficiency M-MDSCs were determined by flow cytometry and CFSE T cell proliferation assays. mTOR deficiency M-MDSCs intracellular autophagy levels were determined by western blot and Electron microscopy. RNAseq analysis was performed for WT and mTOR-deficient M-MDSC cells. Cervical cardiac transplantation model mice were generated. ELISA were performed for control mice, model mice, WT MDSCs infusion model mice and mTOR-deficient MDSCs infusion model mice to examine the inflammatory cytokines in the recipients mice serum. Flow cytometry and immunohistochemistry were performed to determine mTOR-deficient MDSCs induced immune tolerance. Results: mTOR deficiency could promote M-MDSCs differentiation and enhance intracellular autophagy levels in vivo and in vitro. mTOR deficiency also enhance the immunosuppressive function of M-MDSCs. In addition, infusing mTOR deficiency M-MDSCs could also prolong cardiac allograft survival and establish immune tolerance in recipient mice by inhibiting T cell activation and inducing Tregs. Conclusion: mTOR-deficiency enhances M-MDSCs cells autophagy and immunosuppressive function and prolongs mice cardiac allograft survival.

2021-02-27 | GSE167594 | GEO

Distinct population of immune suppressive macrophages differentiate from monocytic myeloid-derived suppressor cells in cancer

Project description:Distinct population of immune suppressive macrophages differentiate from monocytic myeloid-derived suppressor cells in 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:The present data suggest that M-MDSC, play a predominant role in forming the immunosuppressive microenvironment in GC.

2024-01-22 | GSE231539 | GEO

Distinct population of immune suppressive macrophages differentiate from monocytic myeloid-derived suppressor cells in cancer

Project description:Here, we report that functional heterogeneity of macrophages in cancer could be determined by the nature of their precursors: monocytes (Mon) and monocytic myeloid-derived suppressor cells (M-MDSC). Macrophages differentiated from M-MDSC, but not from Mon were immune suppressive with genomic profile matching that of M-MDSC. Immune suppressive activity of M-MDSC derived macrophages was dependent on the persistent expression of S100A9 protein in these cells. S100A9 also promoted M2 polarization of macrophages. Tissue resident and Mon derived macrophages lacked expression of this protein. S100A9 dependent immune suppressive activity of macrophage was mediated via transcription factor CEBP/β. The presence of S100A9 positive macrophages in tumor tissues was associated with shorter survival in patients with head and neck cancer and poor response to PD-1 antibody treatment in patients with metastatic melanoma. Thus, this study revealed the pathway of the development of immune suppressive macrophages and suggested approach to their selective targeting.

2020-12-14 | GSE162353 | GEO

RNASeq analysis of Myeloid Derived Suppressor Cells (MDSCs) from MC38 syngeneic mice to study their role on tumour intrinsic pathways (STING/IFN) for driving ceralasertib (AZD6738) efficacy

Project description:Understanding MoA of ceralasertib (AZD6738) in driving efficacy through immune regulation via polymorphonuclear-myeloid derived suppressor cells (PMN-MDSC) and monocytic-myeloid derived suppressor cells (M-MDSC) on tumour intrinsic pathways (STING/IFN) for AZD6738 driven efficacy. Animals were treated only for 7 days and left for further 7 days without treatment. We compared cells against Vehicle and spleen derived ( naive) as a positive control.

2024-01-30 | E-MTAB-13707 | biostudies-arrayexpress

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.

2023-01-10 | GSE218704 | GEO

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