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VISTA targeting of T cell quiescence and myeloid suppression overcomes adaptive resistance

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE206835 | GEO | 2022/06/26

REPOSITORIES: GEO

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	GSE206835_RAW.tar	Raw
	GSE206835_Seurat_object_AH1_CD8T.rds.gz	Other
	GSE206835_Seurat_object_CD45_lymphoid.rds.gz	Other
	GSE206835_Seurat_object_CD45_myeloid.rds.gz	Other

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VISTA Targeting of T-cell Quiescence and Myeloid Suppression Overcomes Adaptive Resistance.

Project description: Not available

| S-EPMC10544831 | biostudies-literature

VISTA immune-checkpoint blunts radiotherapy induced anti-tumor immune response

Project description:Radiotherapy (RT) is a cornerstone treatment for cancers like head and neck cancer (HNC), but it can also unintentionally activate immune-suppressive myeloid cells, which may limit its effectiveness. This study explores the role of the immune checkpoint protein VISTA, which is found at high levels on myeloid cells in both mouse and human HNC tumors. RT further increases the number of VISTA-positive myeloid cells in the tumor and bloodstream. Mice lacking VISTA responded better to RT, with their immune cells–especially macrophages and neutrophils–shifting toward anti-tumor behavior, as revealed by single-cell RNA sequencing. Importantly, combining RT with anti-VISTA antibodies significantly shrank tumors in several cancer models (HNC, breast, colorectal), more so than either treatment alone. This combination also boosted the overall immune response, improving T cell activity through reprogramming of myeloid cells. These findings suggest that blocking VISTA could make RT more effective by counteracting immune suppression in the tumor environment.

2025-05-29 | GSE295914 | GEO

Role of VISTA in ILC2-mediated airway hyperreactivity

Project description:Type-2 innate lymphoid cells (ILC2s) play a pivotal role in the development of airway hyperresponsiveness (AHR). However, the regulatory mechanisms governing ILC2 function remain inadequately explored. This study uncovers V-domain Ig suppressor of T cell activation (VISTA) as an inhibitory immune checkpoint crucial for modulating ILC2-driven lung inflammation. VISTA is upregulated in activated pulmonary ILC2s and plays a key role in regulating lung inflammation, as VISTA-deficient ILC2s demonstrate increased proliferation and function, resulting in elevated type-2 cytokine production and exacerbation of AHR. Mechanistically, VISTA stimulation activates Forkhead box O1 (FOXO1), leading to modulation of ILC2 proliferation and function. The suppressive effects of FOXO1 on ILC2 effector function were confirmed using FOXO1 inhibitors and activators. Moreover, VISTA-deficient ILC2s exhibit enhanced fatty acid oxidation and oxidative phosphorylation to meet their high energy demands. Therapeutically, VISTA agonist treatment reduces ILC2 function both ex vivo and in vivo, significantly alleviating ILC2-driven AHR. Our murine findings were validated in human ILC2s, where a VISTA agonist reduces their function ex vivo and in a humanized mouse model of AHR. Our studies unravel VISTA as a novel immune checkpoint for ILC2 regulation via the FOXO1 pathway, presenting potential therapeutic strategies for allergic asthma by modulating ILC2 responses.

2025-02-18 | GSE271999 | GEO

LRIG1 engages ligand VISTA and impairs tumor-specific CD8+ T cell responses

Project description:Cancer immunotherapies boost antitumor immunity and improve the survival of cancer patients. V-domain Immunoglobulin Suppressor of T cell Activation (VISTA) is an immune 20 checkpoint target but presents elusive signaling mechanisms. We report a novel VISTA binding partner, Leucine-Rich Repeats and Immunoglobulin Like Domains 1 (LRIG1), which acts as an inhibitory receptor by engaging VISTA and suppressing T cell receptor signaling pathways. Mice with T cell-specific LRIG1 deletion developed superior antitumor T cell responses. Mechanistically, LRIG1-deficient tumor-specific CD8+ cytotoxic T cells (CTLs) exhibited longer 25 persistence due to improved expansion and survival and greater effector function. Sustained tumor control was also associated with a reduction of quiescent CTLs (TCF1+ CD62Lhi PD-1low) and a reciprocal increase in progenitor and memory-like CTLs (TCF1+ PD-1+). In human melanoma, an elevated LRIG1 expression on tumor-infiltrating CD8+ CTLs correlated with resistance to immunotherapies. Taken together, these results delineate the role of LRIG1 as an inhibitory 30 immune checkpoint receptor and propose a rationale for targeting the VISTA/LRIG1 axis for cancer immunotherapy.

2024-10-17 | PXD050084 | Pride

VISTA targeting of T cell quiescence and myeloid suppression overcomes adaptive resistance

Project description:VISTA targeting of T cell quiescence and myeloid suppression overcomes adaptive resistance

| PRJNA852275 | ENA

Inhibition of lung tumorigenesis by a small molecule CA170 targeting the immune checkpoint protein VISTA

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

VISTA Drives Pancreatic Tumor Progression Through Modulation of The Tumor-Associated Macrophage Polarity

Project description:Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies due to its highly immunosuppressive tumor microenvironment (TME), which limits effective therapeutic interventions. Here, we demonstrate that V-domain immunoglobulin suppressor of T cell activation (VISTA) plays a crucial role in orchestrating macrophage polarity within the PDAC TME. Using murine PDAC models, we show that VISTA deficiency markedly impairs tumor growth, leading to reduced tumor volumes and prolonged survival. Mechanistically, VISTA loss reprograms tumor-associated macrophages (TAMs) from an immunosuppressive, secreted phosphoprotein 1(SPP1) expressing phenotype to a pro-inflammatory, C-X-C motif chemokine ligand 9 (CXCL9) expressing subtype. This switch enhances the recruitment of C-X-C motif chemokine receptor 3 (CXCR3) positive CD8+ T cells, reducing their exhaustion and sustaining their cytotoxic activity. Additionally, VISTA-deficient TAMs exhibit increased antigen cross-presentation, further amplifying CD8+ T cell response against tumors. These findings are corroborated by human single cell RNA-seq datasets, which suggest a conserved mechanism of VISTA-mediated immune modulation in PDAC TME. By elucidating the upstream role of VISTA in driving Cxcl9:Spp1 macrophage polarity and T cell dynamics, this study highlights VISTA inhibition as a promising therapeutic strategy to reshape the TME, augment CD8+ T cell function, and enhance anti-tumor immunity in PDAC.

2026-02-21 | GSE282101 | GEO

RNA of murine macrophages and neutrophils treated with LPS and VISTA

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

VISTA is an activating receptor that binds the proteoglycan Syndecan-2 on monocytes.

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

VISTA immune-checkpoint blunts radiotherapy induced anti-tumor immune response

Project description:VISTA immune-checkpoint blunts radiotherapy induced anti-tumor immune response

| PRJNA1256782 | ENA