Inhibition of lung tumorigenesis by a small molecule CA170 targeting the immune checkpoint protein VISTA
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ABSTRACT:
PROVIDER: PRJNA734900 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14715739.fastq.gz | Fastqsanger.gz | |||
| SRR14715740.fastq.gz | Fastqsanger.gz | |||
| SRR14715741_1.fastq.gz | Fastqsanger.gz | |||
| SRR14715741_2.fastq.gz | Fastqsanger.gz | |||
| SRR14715742_1.fastq.gz | Fastqsanger.gz |
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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: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
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: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
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
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.
| S-EPMC8302676 | biostudies-literature
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:VISTA immune-checkpoint blunts radiotherapy induced anti-tumor immune response
| PRJNA1256782 | ENA
Project description:BackgroundCancer immunotherapy has gained increasing popularity as a novel approach to treat cancer. A member of the B7 family, V-domain immunoglobulin suppressor of T-cell activation (VISTA) is a novel immune checkpoint that regulates a broad spectrum of immune responses. VISTA is an acidic pH-selective ligand for P-selectin glycoprotein ligand-1(PSGL-1). CA-170, a first-in-class small-molecule dual antagonist of VISTA/PD-L1, was collaboratively developed by Aurigene Discovery Technologies Limited and Curis, Inc. It is currently in Phase I clinical trial.ResultsIn this study, we develop homology modeling for the VISTA 3D structure and subsequent virtual screening for VISTA small-molecule hit ligands. Visualization of the binding postures of docked ligands with the VISTA protein indicates that some small molecular compounds target VISTA. The ability of antagonist to disrupt immune checkpoint VISTA pathways was investigated though functional studies in vitro.ConclusionsAffinity active molecule for VISTA was obtained through virtual screening, and the antagonist compound activity to VISTA was assayed in cellular level. We reported a small molecule with high VISTA affinity as antagonist, providing ideas for development VISTA-targeted small molecule compound in cancer immunotherapy.
| S-EPMC8359099 | biostudies-literature
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