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

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Abstract

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.

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Abbreviations

CTLA-4:

Cytotoxic T lymphocyte-associated antigen 4

HPV:

Human papillomavirus

MDSCs:

Myeloid-derived suppressor cells

OSCC:

Oral squamous cell carcinoma

PD-1:

Programmed death-1

PD-L1:

Programmed death ligand 1

TAMs:

Tumor-associated macrophages

TPF:

Cisplatin, docetaxel and fluorouracil

Tregs:

Regulatory T cells

VH CH:

VISTA high CD8 high

VH CL:

VISTA high CD8 low

VISTA:

V-domain Ig suppressor of T cell activation

VL CH:

VISTA low CD8 high

VL CL:

VISTA low CD8 low

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Acknowledgements

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.

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    Authors and Affiliations

    1. The State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory of Oral Biomedicine, Ministry of Education, Wuhan University, Wuhan, China

      Lei Wu, Wei-Wei Deng, Cong-Fa Huang, Lin-Lin Bu, Guang-Tao Yu, Liang Mao, Wen-Feng Zhang, Bing Liu & Zhi-Jun Sun

    2. Department of Oral Maxillofacial-Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan, China

      Wen-Feng Zhang, Bing Liu & Zhi-Jun Sun

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

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    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). https://doi.org/10.1007/s00262-017-1968-0

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