VISTA (protein) explained

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.^{[1] [2] [3]}

Structure and function

VISTA is approximately 50 kDa and belongs to the immunoglobulin superfamily and has one IgV domain.^[4]

VISTA is part of the B7 family, is primarily expressed in white blood cells and its transcription is partially controlled by p53.^[5] There is evidence that VISTA can act as both a ligand^[6] and a receptor^[7] on T cells to inhibit T cell effector function and maintain peripheral tolerance. Similarly, VISTA and TIM-3 may co-exist on macrophages infiltrating different human and mouse tumours where they can co-regulate immunotherapy resistance.^[8]

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^[9] and squamous cell carcinoma.^[10] It is also up-regulated in tumour-associated macrophages in various malignancies, including melanoma, especially in immunotherapy-resistant human context.

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.^[11]

As a drug target

There is an ongoing cancer immunotherapy clinical trial for a monoclonal antibody targeting VISTA in advanced cancer.^[12] Preliminary results of the phase I clinical trial show good safety tolerance and anti-cancer activity in patients with advanced tumours.^[13] 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.^[14]

Further reading

• Colland F, Jacq X, Trouplin V, Mougin C, Groizeleau C, Hamburger A, Meil A, Wojcik J, Legrain P, Gauthier JM . Functional proteomics mapping of a human signaling pathway . Genome Research . 14 . 7 . 1324–1332 . July 2004 . 15231748 . 442148 . 10.1101/gr.2334104 .
• Zhang Z, Henzel WJ . Signal peptide prediction based on analysis of experimentally verified cleavage sites . Protein Science . 13 . 10 . 2819–2824 . October 2004 . 15340161 . 2286551 . 10.1110/ps.04682504 .
• Wan D, Gong Y, Qin W, Zhang P, Li J, Wei L, Zhou X, Li H, Qiu X, Zhong F, He L, Yu J, Yao G, Jiang H, Qian L, Yu Y, Shu H, Chen X, Xu H, Guo M, Pan Z, Chen Y, Ge C, Yang S, Gu J . 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 . November 2004 . 15498874 . 524842 . 10.1073/pnas.0404089101 . free . 2004PNAS..10115724W .
• Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M . Towards a proteome-scale map of the human protein-protein interaction network . Nature . 437 . 7062 . 1173–1178 . October 2005 . 16189514 . 10.1038/nature04209 . 4427026 . 2005Natur.437.1173R .

Notes and References

1. Le Mercier I, Lines JL, Noelle RJ . Beyond CTLA-4 and PD-1, the Generation Z of Negative Checkpoint Regulators . Frontiers in Immunology . 6 . 418 . August 2015 . 26347741 . 4544156 . 10.3389/fimmu.2015.00418 . free .
2. Clark HF, Gurney AL, Abaya E, Baker K, Baldwin D, Brush J, Chen J, Chow B, Chui C, Crowley C, Currell B, Deuel B, Dowd P, Eaton D, Foster J, Grimaldi C, Gu Q, Hass PE, Heldens S, Huang A, Kim HS, Klimowski L, Jin Y, Johnson S, Lee J, Lewis L, Liao D, Mark M, Robbie E, Sanchez C, Schoenfeld J, Seshagiri S, Simmons L, Singh J, Smith V, Stinson J, Vagts A, Vandlen R, Watanabe C, Wieand D, Woods K, Xie MH, Yansura D, Yi S, Yu G, Yuan J, Zhang M, Zhang Z, Goddard A, Wood WI, Godowski P, Gray A . 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 . October 2003 . 12975309 . 403697 . 10.1101/gr.1293003 .
3. Web site: Entrez Gene: C10orf54 chromosome 10 open reading frame 54.
4. Yoon KW, Byun S, Kwon E, Hwang SY, Chu K, Hiraki M, Jo SH, Weins A, Hakroush S, Cebulla A, Sykes DB, Greka A, Mundel P, Fisher DE, Mandinova A, Lee SW . Control of signaling-mediated clearance of apoptotic cells by the tumor suppressor p53 . Science . 349 . 6247 . 1261669 . July 2015 . 26228159 . 5215039 . 10.1126/science.1261669 .
5. Wang L, Rubinstein R, Lines JL, Wasiuk A, Ahonen C, Guo Y, Lu LF, Gondek D, Wang Y, Fava RA, Fiser A, Almo S, Noelle RJ . VISTA, a novel mouse Ig superfamily ligand that negatively regulates T cell responses . The Journal of Experimental Medicine . 208 . 3 . 577–592 . March 2011 . 21383057 . 3058578 . 10.1084/jem.20100619 .
6. Lines JL, Pantazi E, Mak J, Sempere LF, Wang L, O'Connell S, Ceeraz S, Suriawinata AA, Yan S, Ernstoff MS, Noelle R . VISTA is an immune checkpoint molecule for human T cells . Cancer Research . 74 . 7 . 1924–1932 . April 2014 . 24691993 . 3979527 . 10.1158/0008-5472.CAN-13-1504 .
7. Flies DB, Han X, Higuchi T, Zheng L, Sun J, Ye JJ, Chen L . Coinhibitory receptor PD-1H preferentially suppresses CD4⁺ T cell-mediated immunity . The Journal of Clinical Investigation . 124 . 5 . 1966–1975 . May 2014 . 24743150 . 4001557 . 10.1172/JCI74589 .
8. Vanmeerbeek I, Naulaerts S, Sprooten J, Laureano RS, Govaerts J, Trotta R, Pretto S, Zhao S, Cafarello ST, Verelst J, Jacquemyn M, Pociupany M, Boon L, Schlenner SM, Tejpar S, Daelemans D, Mazzone M, Garg AD . Targeting conserved TIM3⁺VISTA⁺ tumor-associated macrophages overcomes resistance to cancer immunotherapy . Science Advances . 10 . 29 . eadm8660 . July 2024 . 39028818 . 11259173 . 10.1126/sciadv.adm8660 .
9. Le Mercier I, Chen W, Lines JL, Day M, Li J, Sergent P, Noelle RJ, Wang L . VISTA Regulates the Development of Protective Antitumor Immunity . Cancer Research . 74 . 7 . 1933–1944 . April 2014 . 24691994 . 4116689 . 10.1158/0008-5472.CAN-13-1506 .
10. Kondo Y, Ohno T, Nishii N, Harada K, Yagita H, Azuma M . Differential contribution of three immune checkpoint (VISTA, CTLA-4, PD-1) pathways to antitumor responses against squamous cell carcinoma . Oral Oncology . 57 . 54–60 . June 2016 . 27208845 . 10.1016/j.oraloncology.2016.04.005 .
11. Bharaj P, Chahar HS, Alozie OK, Rodarte L, Bansal A, Goepfert PA, Dwivedi A, Manjunath N, Shankar P . Characterization of programmed death-1 homologue-1 (PD-1H) expression and function in normal and HIV infected individuals . PLOS ONE . 9 . 10 . e109103 . October 3, 2014 . 25279955 . 4184823 . 10.1371/journal.pone.0109103 . 2014PLoSO...9j9103B . free .
12. Web site: A Study of Safety, Pharmacokinetics, Pharmacodynamics of JNJ-61610588 in Participants With Advanced Cancer . September 25, 2016.
13. Calvo . Emiliano . 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 . February 26, 2018 . 10.1200/JCO.2018.36.5_suppl.58 .
14. Web site: A Study of CA-170 (Oral PD-L1, PD-L2 and VISTA Checkpoint Antagonist) in Patients With Advanced Tumors and Lymphomas . September 26, 2016.