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

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

PROVIDER: PRJNA734900 | ENA |

REPOSITORIES: ENA

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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

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

Project description: Not available

| S-EPMC8302676 | biostudies-literature

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

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

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

Identification of active small-molecule modulators targeting the novel immune checkpoint VISTA.

Project description: Not available

| S-EPMC8359099 | biostudies-literature

VISTA re-programs macrophage biology through the combined regulation of tolerance and anti-inflammatory pathways

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

Autophagy Inhibition via Targeting of PIKfyve Potentiates Immune Checkpoint Blockade in Prostate Cancer Therapy

Project description:To understand the tumor microenvironment changes in terms of transcriptome upon PIKfyve inhibition by small molecule ESK981 and the immune checkpoint inhibitor anti-PD-1 in Myc-CaP syngeneic mouse model.

2021-05-18 | GSE174644 | GEO

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

Kidney VISTA prevents IFNγ-IL-9 axis-mediated tubulointerstitial fibrosis after acute glomerular injury

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

VISTA is an immune checkpoint molecule for human T cells.

Project description: Not available

| S-EPMC3979527 | biostudies-literature