Skip to main content


Log in

Expression of VISTA correlated with immunosuppression and synergized with CD8 to predict survival in human oral squamous cell carcinoma

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript


V-domain Ig suppressor of T cell activation (VISTA), a novel immune checkpoint regulatory molecule, suppresses T cell mediated immune responses. The aim of the present study was to profile the immunological expression, clinical significance and correlation of VISTA in human oral squamous cell carcinoma (OSCC). Human tissue microarrays, containing 165 primary OSCCs, 48 oral epithelial dysplasias and 43 normal oral mucosae, were applied to investigate the expression levels of VISTA, CD8, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed death ligand 1 (PD-L1), PI3Kα p110, IL13Rα2, phospho-STAT3 at tyrosine 705 (p-STAT3) and myeloid-derived suppressor cell (MDSC) markers (CD11b and CD33) by immunohistochemistry and digital pathology analysis. The results demonstrated that the protein level of VISTA was significantly higher in human OSCC specimens, and that VISTA expression in primary OSCCs was correlated with lymph node status. VISTA expression did not serve as an independent predictor for poor prognosis, while patient subgroup with VISTA high and CD8 low expression (22/165) had significantly poorer overall survival compared with other subgroups based on the multivariate and Cox hazard analyses among the primary OSCC patients in the present cohort. Additionally, the expression of VISTA was significantly correlated with PD-L1, CTLA-4, IL13Rα2, PI3K, p-STAT3, CD11b and CD33 according to Pearson’s correlation coefficient test. Taken together, the results indicated that the VISTA high and CD8 low group, as an immunosuppressive subgroup, might be associated with a poor prognosis in primary OSCC. These findings indicated that VISTA might be a potential immunotherapeutic target in OSCC treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others



Cytotoxic T lymphocyte-associated antigen 4


Human papillomavirus


Myeloid-derived suppressor cells


Oral squamous cell carcinoma


Programmed death-1


Programmed death ligand 1


Tumor-associated macrophages


Cisplatin, docetaxel and fluorouracil


Regulatory T cells


VISTA high CD8 high


VISTA high CD8 low


V-domain Ig suppressor of T cell activation


VISTA low CD8 high


VISTA low CD8 low


  1. Leemans CR, Braakhuis BJ, Brakenhoff RH (2011) The molecular biology of head and neck cancer. Nat Rev Cancer 11(1):9–22. doi:10.1038/nrc2982

    Article  CAS  PubMed  Google Scholar 

  2. Smith RB, Sniezek JC, Weed DT, Wax MK (2007) Utilization of free tissue transfer in head and neck surgery. Otolaryngol Head Neck Surg 137(2):182–191. doi:10.1016/j.otohns.2007.04.011

    Article  PubMed  Google Scholar 

  3. Vergeer MR, Doornaert PA, Rietveld DH, Leemans CR, Slotman BJ, Langendijk JA (2009) Intensity-modulated radiotherapy reduces radiation-induced morbidity and improves health-related quality of life: results of a nonrandomized prospective study using a standardized follow-up program. Int J Radiat Oncol Biol Phys 74(1):1–8. doi:10.1016/j.ijrobp.2008.07.059

    Article  PubMed  Google Scholar 

  4. Boscolo-Rizzo P, Maronato F, Marchiori C, Gava A, Da Mosto MC (2008) Long-term quality of life after total laryngectomy and postoperative radiotherapy versus concurrent chemoradiotherapy for laryngeal preservation. Laryngoscope 118(2):300–306. doi:10.1097/MLG.0b013e31815a9ed3

    Article  PubMed  Google Scholar 

  5. Hashemi-Sadraei N, Sikora AG, Brizel DM (2016) Immunotherapy and checkpoint inhibitors in recurrent and metastatic head and neck cancer. Am Soc Clin Oncol Educ Book 35:e277–e282. doi:10.14694/EDBK_157801

    Article  Google Scholar 

  6. Lesterhuis WJ, Haanen JB, Punt CJ (2011) Cancer immunotherapy—revisited. Nat Rev Drug Discov 10(8):591–600. doi:10.1038/nrd3500

    Article  CAS  PubMed  Google Scholar 

  7. Kloke BP, Mahr A, Jabulowsky RA, Kutscher S, Rae R, Britten CM (2015) Cancer immunotherapy achieves breakthrough status: 12th annual meeting of the association for cancer immunotherapy (CIMT), Mainz, Germany, May 6–8, 2014. Cancer Immunol Immunother 64(7):923–930. doi:10.1007/s00262-014-1643-7

    Article  PubMed  Google Scholar 

  8. Topalian SL, Drake CG, Pardoll DM (2015) Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27(4):450–461. doi:10.1016/j.ccell.2015.03.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Greenwald RJ, Freeman GJ, Sharpe AH (2005) The B7 family revisited. Annu Rev Immunol 23:515–548. doi:10.1146/annurev.immunol.23.021704.115611

    Article  PubMed  Google Scholar 

  10. Blank C, Gajewski TF, Mackensen A (2005) Interaction of PD-L1 on tumor cells with PD-1 on tumor-specific T cells as a mechanism of immune evasion: implications for tumor immunotherapy. Cancer Immunol Immunother 54(4):307–314. doi:10.1007/s00262-004-0593-x

    Article  CAS  PubMed  Google Scholar 

  11. Simeone E, Ascierto PA (2012) Immunomodulating antibodies in the treatment of metastatic melanoma: the experience with anti-CTLA-4, anti-CD137, and anti-PD1. J Immunotoxicol 9(3):241–247. doi:10.3109/1547691X.2012.678021

    Article  CAS  PubMed  Google Scholar 

  12. Gunturi A, McDermott DF (2014) Potential of new therapies like anti-PD1 in kidney cancer. Curr Treat Options Oncol 15(1):137–146. doi:10.1007/s11864-013-0268-y

    Article  PubMed  Google Scholar 

  13. Westin JR, Chu F, Zhang M, Fayad LE, Kwak LW, Fowler N, Romaguera J, Hagemeister F, Fanale M, Samaniego F, Feng L, Baladandayuthapani V, Wang Z, Ma W, Gao Y, Wallace M, Vence LM, Radvanyi L, Muzzafar T, Rotem-Yehudar R, Davis RE, Neelapu SS (2014) Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, phase 2 trial. Lancet Oncol 15(1):69–77. doi:10.1016/S1470-2045(13)70551-5

    Article  CAS  PubMed  Google Scholar 

  14. 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 (2011) VISTA, a novel mouse Ig superfamily ligand that negatively regulates T cell responses. J Exp Med 208(3):577–592. doi:10.1084/jem.20100619

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Flies DB, Wang S, Xu H, Chen L (2011) Cutting edge: a monoclonal antibody specific for the programmed death-1 homolog prevents graft-versus-host disease in mouse models. J Immunol 187(4):1537–1541. doi:10.4049/jimmunol.1100660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Le Mercier I, Chen W, Lines JL, Day M, Li J, Sergent P, Noelle RJ, Wang L (2014) VISTA regulates the development of protective antitumor immunity. Cancer Res 74(7):1933–1944. doi:10.1158/0008-5472.CAN-13-1506

    Article  CAS  PubMed  Google Scholar 

  17. Wang L, Le Mercier I, Putra J, Chen W, Liu J, Schenk AD, Nowak EC, Suriawinata AA, Li J, Noelle RJ (2014) Disruption of the immune-checkpoint VISTA gene imparts a proinflammatory phenotype with predisposition to the development of autoimmunity. Proc Natl Acad Sci USA 111(41):14846–14851. doi:10.1073/pnas.1407447111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhong LP, Zhang CP, Ren GX, Guo W, William WN Jr, Sun J, Zhu HG, Tu WY, Li J, Cai YL, Wang LZ, Fan XD, Wang ZH, Hu YJ, Ji T, Yang WJ, Ye WM, Li J, He Y, Wang YA, Xu LQ, Wang BS, Kies MS, Lee JJ, Myers JN, Zhang ZY (2013) Randomized phase III trial of induction chemotherapy with docetaxel, cisplatin, and fluorouracil followed by surgery versus up-front surgery in locally advanced resectable oral squamous cell carcinoma. J Clin Oncol 31(6):744–751. doi:10.1200/JCO.2012.43.8820

    Article  CAS  PubMed  Google Scholar 

  19. Bu LL, Zhao ZL, Liu JF, Ma SR, Huang CF, Liu B, Zhang WF, Sun ZJ (2015) STAT3 blockade enhances the efficacy of conventional chemotherapeutic agents by eradicating head neck stemloid cancer cell. Oncotarget 6(39):41944–41958. doi:10.18632/oncotarget.5986

    PubMed  PubMed Central  Google Scholar 

  20. Lyford-Pike S, Peng S, Young GD, Taube JM, Westra WH, Akpeng B, Bruno TC, Richmon JD, Wang H, Bishop JA, Chen L, Drake CG, Topalian SL, Pardoll DM, Pai SI (2013) Evidence for a role of the PD-1:PD-L1 pathway in immune resistance of HPV-associated head and neck squamous cell carcinoma. Cancer Res 73(6):1733–1741. doi:10.1158/0008-5472.CAN-12-2384

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Czerninski R, Amornphimoltham P, Patel V, Molinolo AA, Gutkind JS (2009) Targeting mammalian target of rapamycin by rapamycin prevents tumor progression in an oral-specific chemical carcinogenesis model. Cancer Prev Res (Phila) 2(1):27–36. doi:10.1158/1940-6207.CAPR-08-0147

    Article  CAS  Google Scholar 

  22. Sun ZJ, Zhang L, Hall B, Bian Y, Gutkind JS, Kulkarni AB (2012) Chemopreventive and chemotherapeutic actions of mTOR inhibitor in genetically defined head and neck squamous cell carcinoma mouse model. Clin Cancer Res 18(19):5304–5313. doi:10.1158/1078-0432.CCR-12-1371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ma SR, Wang WM, Huang CF, Zhang WF, Sun ZJ (2015) Anterior gradient protein 2 expression in high grade head and neck squamous cell carcinoma correlated with cancer stem cell and epithelial mesenchymal transition. Oncotarget 6(11):8807–8821. doi:10.18632/oncotarget.3556

    Article  PubMed  PubMed Central  Google Scholar 

  24. Rhodes DR, Kalyana-Sundaram S, Mahavisno V, Varambally R, Yu J, Briggs BB, Barrette TR, Anstet MJ, Kincead-Beal C, Kulkarni P, Varambally S, Ghosh D, Chinnaiyan AM (2007) Oncomine 3.0: genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles. Neoplasia 9(2):166–180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Peng CH, Liao CT, Peng SC, Chen YJ, Cheng AJ, Juang JL, Tsai CY, Chen TC, Chuang YJ, Tang CY, Hsieh WP, Yen TC (2011) A novel molecular signature identified by systems genetics approach predicts prognosis in oral squamous cell carcinoma. PLoS One 6(8):e23452. doi:10.1371/journal.pone.0023452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Chen HH, Huang N, Chen YM, Chen TJ, Chou P, Lee YL, Chou YJ, Lan JL, Lai KL, Lin CH, Chen DY (2013) Association between a history of periodontitis and the risk of rheumatoid arthritis: a nationwide, population-based, case-control study. Ann Rheum Dis 72(7):1206–1211. doi:10.1136/annrheumdis-2012-201593

    Article  PubMed  Google Scholar 

  27. Yu GT, Bu LL, Huang CF, Zhang WF, Chen WJ, Gutkind JS, Kulkarni AB, Sun ZJ (2015) PD-1 blockade attenuates immunosuppressive myeloid cells due to inhibition of CD47/SIRPalpha axis in HPV negative head and neck squamous cell carcinoma. Oncotarget 6(39):42067–42080. doi:10.18632/oncotarget.5955

    PubMed  PubMed Central  Google Scholar 

  28. Pages F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R, Mlecnik B, Kirilovsky A, Nilsson M, Damotte D, Meatchi T, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Galon J (2005) Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 353(25):2654–2666. doi:10.1056/NEJMoa051424

    Article  CAS  PubMed  Google Scholar 

  29. Workel HH, Komdeur FL, Wouters MC, Plat A, Klip HG, Eggink FA, Wisman GB, Arts HJ, Oonk MH, Mourits MJ, Yigit R, Versluis M, Duiker EW, Hollema H, de Bruyn M, Nijman HW (2016) CD103 defines intraepithelial CD8+ PD1+ tumour-infiltrating lymphocytes of prognostic significance in endometrial adenocarcinoma. Eur J Cancer 60:1–11. doi:10.1016/j.ejca.2016.02.026

    Article  CAS  PubMed  Google Scholar 

  30. Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, Higuchi T, Yagi H, Takakura K, Minato N, Honjo T, Fujii S (2007) Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci USA 104(9):3360–3365. doi:10.1073/pnas.0611533104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Nakano O, Sato M, Naito Y, Suzuki K, Orikasa S, Aizawa M, Suzuki Y, Shintaku I, Nagura H, Ohtani H (2001) Proliferative activity of intratumoral CD8(+) T-lymphocytes as a prognostic factor in human renal cell carcinoma: clinicopathologic demonstration of antitumor immunity. Cancer Res 61(13):5132–5136

    CAS  PubMed  Google Scholar 

  32. Schumacher K, Haensch W, Roefzaad C, Schlag PM (2001) Prognostic significance of activated CD8(+) T cell infiltrations within esophageal carcinomas. Cancer Res 61(10):3932–3936

    CAS  PubMed  Google Scholar 

  33. Ferris RL (2015) Immunology and Immunotherapy of Head and Neck Cancer. J Clin Oncol 33(29):3293–3304. doi:10.1200/JCO.2015.61.1509

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. De Costa AM, Schuyler CA, Walker DD, Young MR (2012) Characterization of the evolution of immune phenotype during the development and progression of squamous cell carcinoma of the head and neck. Cancer Immunol Immunother 61(6):927–939. doi:10.1007/s00262-011-1154-8

    Article  PubMed  Google Scholar 

  35. Lines JL, Pantazi E, Mak J, Sempere LF, Wang L, O’Connell S, Ceeraz S, Suriawinata AA, Yan S, Ernstoff MS, Noelle R (2014) VISTA is an immune checkpoint molecule for human T cells. Cancer Res 74(7):1924–1932. doi:10.1158/0008-5472.CAN-13-1504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hall B, Nakashima H, Sun ZJ, Sato Y, Bian Y, Husain SR, Puri RK, Kulkarni AB (2013) Targeting of interleukin-13 receptor alpha2 for treatment of head and neck squamous cell carcinoma induced by conditional deletion of TGF-beta and PTEN signaling. J Transl Med 11:45. doi:10.1186/1479-5876-11-45

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Fichtner-Feigl S, Strober W, Kawakami K, Puri RK, Kitani A (2006) IL-13 signaling through the IL-13alpha2 receptor is involved in induction of TGF-beta1 production and fibrosis. Nat Med 12(1):99–106. doi:10.1038/nm1332

    Article  CAS  PubMed  Google Scholar 

  38. Bu LL, Yu GT, Deng WW, Mao L, Liu JF, Ma SR, Fan TF, Hall B, Kulkarni AB, Zhang WF, Sun ZJ (2016) Targeting STAT3 signaling reduces immunosuppressive myeloid cells in head and neck squamous cell carcinoma. OncoImmunology 5(5):e1130206. doi:10.1080/2162402X.2015.1130206

    Article  PubMed  PubMed Central  Google Scholar 

  39. Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12(4):252–264. doi:10.1038/nrc3239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Liu J, Yuan Y, Chen W, Putra J, Suriawinata AA, Schenk AD, Miller HE, Guleria I, Barth RJ, Huang YH, Wang L (2015) Immune-checkpoint proteins VISTA and PD-1 nonredundantly regulate murine T-cell responses. Proc Natl Acad Sci USA 112(21):6682–6687. doi:10.1073/pnas.1420370112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Yu GT, Bu LL, Zhao YY, Mao L, Deng WW, Wu TF, Zhang WF, Sun ZJ (2016) CTLA4 blockade reduces immature myeloid cells in head and neck squamous cell carcinoma. OncoImmunology 5(6):e1151594. doi:10.1080/2162402X.2016.1151594

    Article  PubMed  PubMed Central  Google Scholar 

Download references


This work was supported by National Natural Science Foundation of China (81672668, 81472528, 81472529, 81672667, 81272963, 81272964). Zhi-Jun Sun was supported by program for new century excellent talents in university (NCET-13-0439), Ministry of Education of the People’s Republic of China.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Zhi-Jun Sun.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

L. Wu and W.-W. Deng have contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 625 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wu, L., Deng, WW., Huang, CF. et al. Expression of VISTA correlated with immunosuppression and synergized with CD8 to predict survival in human oral squamous cell carcinoma. Cancer Immunol Immunother 66, 627–636 (2017).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: