VISTA (protein)

V-domain Ig suppressor of T cell activation (VISTA) is a type I transmembrane protein that functions as an immune checkpoint and is encoded by the VSIR gene.^[5][6][7]

VSIR
Identifiers
Aliases	VSIR, B7-H5, B7H5, GI24, PP2135, SISP1, DD1alpha, VISTA, C10orf54, chromosome 10 open reading frame 54, PD-1H, V-set immunoregulatory receptor, Dies1
External IDs	OMIM: 615608; MGI: 1921298; HomoloGene: 81923; GeneCards: VSIR; OMA:VSIR - orthologs
Gene location (Human) Chr. Chromosome 10 (human)[1] Band 10q22.1 Start 71,747,556 bp[1] End 71,773,520 bp[1]
Gene location (Mouse) Chr. Chromosome 10 (mouse)[2] Band 10|10 B4 Start 60,182,630 bp[2] End 60,208,463 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in granulocyte monocyte blood bone marrow cells spleen appendix right lung tibial nerve apex of heart left uterine tube Top expressed in granulocyte stroma of bone marrow mesenteric lymph nodes tibiofemoral joint decidua spleen white adipose tissue subcutaneous adipose tissue blood ankle More reference expression data BioGPS More reference expression data
Gene ontology Molecular function identical protein binding enzyme binding endopeptidase activator activity Cellular component integral component of membrane membrane plasma membrane Biological process positive regulation of gene expression positive regulation of endopeptidase activity positive regulation of cell migration zymogen activation negative regulation of interferon-gamma production negative regulation of interleukin-10 production negative regulation of interleukin-17 production negative regulation of tumor necrosis factor production positive regulation of regulatory T cell differentiation positive regulation of collagen catabolic process negative regulation of CD4-positive, alpha-beta T cell proliferation negative regulation of CD8-positive, alpha-beta T cell proliferation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 64115 74048 Ensembl ENSG00000107738 ENSMUSG00000020101 UniProt Q9H7M9 Q9D659 RefSeq (mRNA) NM_022153 NM_001159572 NM_028732 RefSeq (protein) NP_071436 NP_001153044 NP_083008 Location (UCSC) Chr 10: 71.75 – 71.77 Mb Chr 10: 60.18 – 60.21 Mb PubMed search [3] [4]
Wikidata
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Structure and function

VISTA is approximately 50 kDa and belongs to the immunoglobulin superfamily and has one IgV domain.^[8][5]

VISTA is part of the B7 family, is primarily expressed in white blood cells and its transcription is partially controlled by p53.^[8][9] There is evidence that VISTA can act as both a ligand^[10] and a receptor^[11] on T cells to inhibit T cell effector function and maintain peripheral tolerance.^[5][8] Similarly, VISTA and TIM-3 may co-exist on macrophages infiltrating different human and mouse tumours where they can co-regulate immunotherapy resistance.^[12]

Clinical significance

VISTA is produced at high levels in tumor-infiltrating lymphocytes, such as myeloid-derived suppressor cells and regulatory T cells, and its blockade with an antibody results in delayed tumor growth in mouse models of melanoma^[13] and squamous cell carcinoma.^[14] It is also up-regulated in tumour-associated macrophages in various malignancies, including melanoma, especially in immunotherapy-resistant human context.^[12]

Monocytes from HIV-infected patients produce higher levels of VISTA compared to uninfected individuals. The increased VISTA levels correlated with an increase in immune activation and a decrease in CD4-positive T cells.^[15]

As a drug target

There are several ongoing cancer immunotherapy clinical trials for a monoclonal antibodies targeting VISTA in advanced cancer.^[16] Preliminary results of the phase I clinical trials show good safety tolerance and anti-cancer activity in patients with advanced tumours.^[17] One promising approach uses an antibody (SNS-101) that only binds to VISTA when the multiple histidine residues of VISTA are protonated inside acid tumors. This approach greatly improves the pharmacokinetics of the anti-VISTA antibody.^[18] Another ongoing clinical trial involves a small molecule that antagonizes the programmed death-ligands 1 and 2 (PD-L1 and PD-L2), and VISTA pathways in patients with advanced solid tumors or lymphomas.^[19]