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
View/Edit Human View/Edit Mouse

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 is an ongoing cancer immunotherapy clinical trial for a monoclonal antibody targeting VISTA in advanced cancer.^[16] Preliminary results of the phase I clinical trial show good safety tolerance and anti-cancer activity in patients with advanced tumours.^[17] 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.^[18]

References

1. GRCh38: Ensembl release 89: ENSG00000107738 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000020101 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Le Mercier I, Lines JL, Noelle RJ (August 2015). "Beyond CTLA-4 and PD-1, the Generation Z of Negative Checkpoint Regulators". Frontiers in Immunology. 6: 418. doi:10.3389/fimmu.2015.00418. PMC 4544156. PMID 26347741.
6. Clark HF, Gurney AL, Abaya E, Baker K, Baldwin D, Brush J, et al. (October 2003). "The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment". Genome Research. 13 (10): 2265–2270. doi:10.1101/gr.1293003. PMC 403697. PMID 12975309.
7. "Entrez Gene: C10orf54 chromosome 10 open reading frame 54".
8. Yoon KW, Byun S, Kwon E, Hwang SY, Chu K, Hiraki M, et al. (July 2015). "Control of signaling-mediated clearance of apoptotic cells by the tumor suppressor p53". Science. 349 (6247): 1261669. doi:10.1126/science.1261669. PMC 5215039. PMID 26228159.
9. Wang L, Rubinstein R, Lines JL, Wasiuk A, Ahonen C, Guo Y, et al. (March 2011). "VISTA, a novel mouse Ig superfamily ligand that negatively regulates T cell responses". The Journal of Experimental Medicine. 208 (3): 577–592. doi:10.1084/jem.20100619. PMC 3058578. PMID 21383057.
10. Lines JL, Pantazi E, Mak J, Sempere LF, Wang L, O'Connell S, et al. (April 2014). "VISTA is an immune checkpoint molecule for human T cells". Cancer Research. 74 (7): 1924–1932. doi:10.1158/0008-5472.CAN-13-1504. PMC 3979527. PMID 24691993.
11. Flies DB, Han X, Higuchi T, Zheng L, Sun J, Ye JJ, et al. (May 2014). "Coinhibitory receptor PD-1H preferentially suppresses CD4⁺ T cell-mediated immunity". The Journal of Clinical Investigation. 124 (5): 1966–1975. doi:10.1172/JCI74589. PMC 4001557. PMID 24743150.
12. Vanmeerbeek I, Naulaerts S, Sprooten J, Laureano RS, Govaerts J, Trotta R, et al. (July 2024). "Targeting conserved TIM3⁺VISTA⁺ tumor-associated macrophages overcomes resistance to cancer immunotherapy". Science Advances. 10 (29): eadm8660. doi:10.1126/sciadv.adm8660. PMC 11259173. PMID 39028818.
13. Le Mercier I, Chen W, Lines JL, Day M, Li J, Sergent P, et al. (April 2014). "VISTA Regulates the Development of Protective Antitumor Immunity". Cancer Research. 74 (7): 1933–1944. doi:10.1158/0008-5472.CAN-13-1506. PMC 4116689. PMID 24691994.
14. Kondo Y, Ohno T, Nishii N, Harada K, Yagita H, Azuma M (June 2016). "Differential contribution of three immune checkpoint (VISTA, CTLA-4, PD-1) pathways to antitumor responses against squamous cell carcinoma". Oral Oncology. 57: 54–60. doi:10.1016/j.oraloncology.2016.04.005. PMID 27208845.
15. Bharaj P, Chahar HS, Alozie OK, Rodarte L, Bansal A, Goepfert PA, et al. (October 3, 2014). "Characterization of programmed death-1 homologue-1 (PD-1H) expression and function in normal and HIV infected individuals". PLOS ONE. 9 (10): e109103. Bibcode:2014PLoSO...9j9103B. doi:10.1371/journal.pone.0109103. PMC 4184823. PMID 25279955.
16. "A Study of Safety, Pharmacokinetics, Pharmacodynamics of JNJ-61610588 in Participants With Advanced Cancer". Retrieved September 25, 2016.
17. Calvo E (February 26, 2018). "Interim results of a phase 1/2 study of JNJ-63723283, an anti-PD-1 monoclonal antibody, in patients with advanced cancers". Journal of Clinical Oncology. 36 (5_suppl): 58. doi:10.1200/JCO.2018.36.5_suppl.58.
18. "A Study of CA-170 (Oral PD-L1, PD-L2 and VISTA Checkpoint Antagonist) in Patients With Advanced Tumors and Lymphomas". Retrieved September 26, 2016.

Further reading

• Colland F, Jacq X, Trouplin V, Mougin C, Groizeleau C, Hamburger A, et al. (July 2004). "Functional proteomics mapping of a human signaling pathway". Genome Research. 14 (7): 1324–1332. doi:10.1101/gr.2334104. PMC 442148. PMID 15231748.
• Zhang Z, Henzel WJ (October 2004). "Signal peptide prediction based on analysis of experimentally verified cleavage sites". Protein Science. 13 (10): 2819–2824. doi:10.1110/ps.04682504. PMC 2286551. PMID 15340161.
• Wan D, Gong Y, Qin W, Zhang P, Li J, Wei L, et al. (November 2004). "Large-scale cDNA transfection screening for genes related to cancer development and progression". Proceedings of the National Academy of Sciences of the United States of America. 101 (44): 15724–15729. Bibcode:2004PNAS..10115724W. doi:10.1073/pnas.0404089101. PMC 524842. PMID 15498874.
• Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, et al. (October 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–1178. Bibcode:2005Natur.437.1173R. doi:10.1038/nature04209. PMID 16189514. S2CID 4427026.

External links

• Overview of all the structural information available in the PDB for UniProt: Q9H7M9 (V-type immunoglobulin domain-containing suppressor of T-cell activation) at the PDBe-KB.