VISTA promotes the metabolism and differentiation of myeloid-derived suppressor cells by STAT3 and polyamine-dependent mechanisms [MDSC_SingleCell]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE244797 | GEO | 2024/01/02
REPOSITORIES: GEO
Similar Datasets
Project description:To investigate the function of VISTA in regulating the differentiation of BM-derived MDSCs under normoxia conditions
2024-01-02 | GSE244545 | GEO
Project description:V-domain immunoglobulin suppressor of T-cell activation (VISTA) has emerged as a unique immunoregulatory receptor on cells of the myeloid lineage. Agonizing VISTA on myeloid cells has recently been demonstrated to have a profound effect on dampening inflammatory responses. VISTA has been proposed to function both as a ligand and as a receptor, yet the role of VISTA as a ligand has been largely ignored. In this experiment, macrophages and neutrophils were isolated from mice and treated with LPS and VISTA to examine the effect of VISTA in dampening acute inflammation.
2022-12-02 | E-MTAB-10856 | biostudies-arrayexpress
Project description:Expressed on cells of the myeloid and lymphoid lineages, V-domain Ig Suppressor of T cell Activation (VISTA) is an emerging target for cancer immunotherapy. Blocking VISTA activates both innate and adaptive immunity to eradicate tumors in mice. Using a tripeptide small molecule antagonist of VISTA CA170, we found that it exhibited potent anticancer efficacy on carcinogen-induced mouse lung tumorigenesis. Remarkably, lung tumor development was almost completely suppressed when CA170 was combined with an MHCII-directed Kras peptide vaccine. Flow cytometry and single-cell RNA sequencing (scRNA-seq) revealed that CA170 increased CD8+ T cell infiltration and enhanced their effector functions by decreasing the tumor infiltration of myeloid-derived suppressor cells (MDSCs) and Regulatory T (Treg) cells, while the Kras vaccine primarily induced expansion of CD4+ effector T cells. VISTA antagonism by CA170 revealed strong efficacy against lung tumorigenesis with broad immunoregulatory functions that influence effector, memory and regulatory T cells, and drives an adaptive T cell tumor-specific immune response that enhances the efficacy of the Kras vaccine.
2021-06-04 | GSE176091 | GEO
Project description:1) BMDMs treated with anti-VISTA under tolerizing and immunizing conditions. 2) Time course analysis of anti-VISTA-induced alterations in human monocytes after anti-VISTA treatment. 3) Time course analysis of anti-VISTA-induced alterations in BMDMs after anti-VISTA treatment. 4) Single cell ATAC-seq of BMDMs tolerized in the presence or IgG or anti-VISTA.
2020-09-05 | GSE157518 | GEO
Project description:VISTA is a premier target for cancer treatment due to its broad expression in many cancer types and enhanced expression upon development of adaptive immune checkpoint resistance. Mechanisms of enhanced anti-tumor immunity were investigated using scRNAseq of the tumor immune infiltrate.
2022-06-26 | GSE206835 | GEO
Project description:Myeloid-derived suppressor cells (MDSCs) are known to contribute to tumour immune escape, studies have verified that MDSCs can induce cancer stem cells (CSCs) and promote tumour immune evasion in breast cancers, cervical cancers and glioblastoma. However, the potential function of MDSCs in regulating CSCs in epithelial ovarian cancer (EOC) progression is unknown. Our results indicated that compared to nonmalignant ovarian patients, EOC patients showed a significantly increased proportion of MDSCs in the peripheral blood. In addition, MDSCs dramatically promoted tumour sphere formation, cell colony formation and CSC accumulation, and MDSCs enhanced the expression of the stemness biomarkers NANOG and c-MYC in EOC cells during co-culture. Moreover, the mechanisms by which MDSCs enhance EOC stemness were further explored, and 586 differentially expressed genes were found in EOC cells co-cultured with or without MDSCs; during co-culture, the expression level of colony stimulating factor 2 (CSF2) was significantly increased in EOC cells co-cultured with MDSCs. Furthermore, the depletion of CSF2 in EOC cells was successfully performed, the promotive effects of MDSCs on EOC cell stemness could be markedly reversed by downregulating CSF2 expression, p-STAT3 signalling pathway molecules were also altered, and the p-STAT3 inhibitor could markedly reverse the promotive effects of MDSCs on EOC cell stemness. In addition, the CSF2 expression level was correlated with EOC clinical staging. Therefore, MDSCs enhance the stemness of epithelial ovarian cancer cells by inducing the CSF2/p-STAT3 signalling pathway. Targeting MDSCs or CSF2 may be a reasonable strategy for enhancing the efficacy of conventional treatments.
2020-12-31 | GSE145374 | GEO
Project description:As indicated by its name, V-domain Ig suppressor of T cell activation (VISTA) is thought to primarily serve as an inhibitory protein that limits immune responses. VISTA-antibodies can dampen the effects of several concomitantly elicited activation signals including T cell receptor (TCR) and Toll-like receptor (TLR) activation, but it is currently unclear if VISTA agonism could singly affect immune cell biology. In this study, we discovered two novel agonistic VISTA antibodies and characterized their effects on human peripheral blood mononuclear cells (PBMC) by scRNA/CITE-seq. Both antibodies agonize VISTA in an Fc-functional manner to elicit transcriptional and functional changes in monocytes consistent with activation. We also used pentameric VISTA to identify Syndecan-2 (Sdc2) and several heparan sulfate proteoglycan (HSPG) synthesis genes as novel regulators of VISTA binding to monocytic cells adding further evidence of bidirectional signaling. Together, our study highlights several novel aspects of VISTA biology that have yet to be uncovered in myeloid cells and serves as a foundation for future research.
2021-05-04 | GSE173747 | 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:Backgrounds: The present study addressed whether V-domain Ig suppressor of T cell activation (VISTA), constitutively expressed in kidney macrophages, has a protective role in tubulointerstitial fibrotic transformation after acute antibody-mediated glomerulonephritis. Methods: Wild-type (WT) and VISTA-deficient (Vsir-/-, KO) mice were treated with nephrotoxic serum to induced acute antibody-mediated glomerulonephritis, and their cytokine and fibrosis profiles were compared. Results: VISTA was highly expressed in kidney macrophages (resident more than infiltrating subset). If VISTA was depleted, tubules suffered further damage after glomerular injury. In damaged Vsir–/– mice, the contact frequency of macrophages with infiltrated T cells increased, and then the immunometabolic characteristics of T cells changed to overproduction of interferon-γ. The Vsir–/– parenchymal tissue cells responded to this altered milieu as more producing interleukin-9, which augmented tubulointerstitial fibrosis and irreversible kidney dysfunction. The blocking antibodies against interferon-γ and interleukin-9 protected above pathological process by VISTA depletion. Conclusions: VISTA is a sentinel protein of kidney macrophages, which prevents tubulointerstitial fibrosis via interferon-γ-interleukin-9 axis after acute antibody-mediated glomerular injury.
2021-08-04 | GSE181163 | GEO
Project description:Myeloid-derived suppressor cells (MDSCs) are key players in immune evasion, tumor progression and metastasis. MDSCs accumulate under various pathological states, and fall into two functionally and phenotypically distinct subsets: polymorphonuclear (PMN)-MDSCs and monocytic (M)-MDSCs. These subsets have been studied extensively in humans and mice, yet to date no study has identified MDSC subsets in dogs with spontaneous tumors. As dogs are an excellent model for human tumor development and progression, we set out to identify PMN-MDSCs and M-MDSCs in clinical canine oncology patients. We identified MDSCs as hypodense MHC class II-CD5-CD21-CD11b+ cells and show for the first time that they can also be subdivided into polymorphonuclear (CADO48A+CD14-) and monocytic (CADO48A-CD14+) subsets. The transcriptomic signatures of PMN-MDSCs and M-MDSCs are distinct from each other and from those of conventional polymorphonuclear (PMN) and monocytic cells, respectively. Notably, bioinformatic analyses reveal a statistically significant similarity between canine and previously published human MDSC gene expression patterns. As in humans, peripheral blood frequencies of canine PMN-MDSCs and M-MDSCs are significantly different in dogs with cancer compared to healthy control dogs (PMN-MDSCs: p < .001; M-MDSCs: p < .01). Furthermore, a comparison of our canine MDSC RNA-seq data with transcriptomic results previously published for human and murine MDSCs highlights five commonly upregulated genes in PMN-MDSCs in all species, suggesting that these genes are evolutionarily conserved and functionally important. Interestingly, one gene has previously been implicated in PMN-MDSC function (MMP8), but four genes (LTF, LCN2, CAMP, EBP41L3) are novel in the context of PMN-MDSCs. Our findings therefore demonstrate for the first time that dogs have two distinct populations of MDSCs, characterized by specific phenotypic and transcriptomic signatures that share key features of human MDSC subsets. Importantly, by leveraging the power of evolution, we have identified additional conserved genes in PMN-MDSCs of multiple species which may play a role in MDSC function. Our findings therefore validate the dog as a model for studying MDSCs in the context of cancer.
2019-03-27 | GSE119353 | GEO