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B7-H4 expression indicates poor prognosis of oral squamous cell carcinoma

Cancer Immunology, Immunotherapy volume 65, pages 1035–1045 (2016)Cite this article

Abstract

Checkpoint blockade therapy utilizing monoclonal antibodies to reactivate T cells and recover their antitumor activity makes an epoch in cancer immunotherapy. The role of B7-H4, a novel negative immune checkpoint, in oral squamous cell carcinoma (OSCC) has still not been elucidated. In this study, tissue samples from human OSCC, which contains 165 primary OSCC, 48 oral epithelial dysplasia and 43 normal oral mucosa specimens, and Tgfbr1/Pten 2cKO mice OSCC model were stained with B7-H4 antibody to analyze the correlations between B7-H4 expression and clinicopathological characteristics. Kaplan–Meier analysis was used to compare the survival of patients with high B7-H4 expression and patients with low B7-H4 expression. We found B7-H4 is highly expressed in human OSCC tissue, and the B7-H4 expression level was associated with the clinicopathological parameters containing pathological grade and lymph node status. Moreover, we confirmed that B7-H4 was overexpressed in Tgfbr1/Pten 2cKO mice OSCC model. Our data also indicated that patients with high B7-H4 expression had poor overall survival compared with those with low B7-H4 expression. Furthermore, this study demonstrated that B7-H4 was positively associated with PD-L1, CD11b, CD33, PI3Kα p110, and p-S6 (S235/236). Taken together, these findings suggest B7-H4 is a potential target in the treatment of OSCC.

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Abbreviations

CTLA-4:

Cytotoxic T lymphocyte-associated protein 4

ESCC:

Esophageal squamous cell carcinoma

MDSCs:

Myeloid-derived suppressor cells

OSCC:

Oral squamous cell carcinoma

PD-1:

Programmed death-1

PD-L1:

Programmed death-ligand 1

RCC:

Renal cell carcinoma

TPF:

Cisplatin, docetaxel, and fluorouracil

Tregs:

Regulatory T cells

WT:

Wild type

References

  1. Stransky N, Egloff AM, Tward AD, Kostic AD, Cibulskis K, Sivachenko A, Kryukov GV, Lawrence MS, Sougnez C, McKenna A, Shefler E, Ramos AH, Stojanov P, Carter SL, Voet D, Cortes ML, Auclair D, Berger MF, Saksena G, Guiducci C, Onofrio RC, Parkin M, Romkes M, Weissfeld JL, Seethala RR, Wang L, Rangel-Escareno C, Fernandez-Lopez JC, Hidalgo-Miranda A, Melendez-Zajgla J, Winckler W, Ardlie K, Gabriel SB, Meyerson M, Lander ES, Getz G, Golub TR, Garraway LA, Grandis JR (2011) The mutational landscape of head and neck squamous cell carcinoma. Science 333(6046):1157–1160. doi:10.1126/science.1208130

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, He J (2016) Cancer statistics in China, 2015. CA Cancer J Clin 66(2):115–132. doi: 10.3322/caac.21338

    Article  Google Scholar 

  3. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90. doi:10.3322/caac.20107

    Article  PubMed  Google Scholar 

  4. Chi AC, Day TA, Neville BW (2015) Oral cavity and oropharyngeal squamous cell carcinoma—an update. CA Cancer J Clin 65(5):401–421. doi:10.3322/caac.21293

    Article  PubMed  Google Scholar 

  5. Gupta S, Kong W, Peng Y, Miao Q, Mackillop WJ (2009) Temporal trends in the incidence and survival of cancers of the upper aerodigestive tract in Ontario and the United States. Int J Cancer 125(9):2159–2165. doi:10.1002/ijc.24533

    CAS  Article  PubMed  Google Scholar 

  6. 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

    CAS  Article  PubMed  Google Scholar 

  7. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366(26):2443–2454. doi:10.1056/NEJMoa1200690

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363(8):711–723. doi:10.1056/NEJMoa1003466

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 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

    CAS  Article  PubMed  Google Scholar 

  10. 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 

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. Carreno BM, Collins M (2003) BTLA: a new inhibitory receptor with a B7-like ligand. Trends Immunol 24(10):524–527

    CAS  Article  PubMed  Google Scholar 

  14. Fauci JM, Straughn JM Jr, Ferrone S, Buchsbaum DJ (2012) A review of B7-H3 and B7-H4 immune molecules and their role in ovarian cancer. Gynecol Oncol 127(2):420–425. doi:10.1016/j.ygyno.2012.08.017

    CAS  Article  PubMed  Google Scholar 

  15. Sica GL, Choi IH, Zhu G, Tamada K, Wang SD, Tamura H, Chapoval AI, Flies DB, Bajorath J, Chen L (2003) B7-H4, a molecule of the B7 family, negatively regulates T cell immunity. Immunity 18(6):849–861

    CAS  Article  PubMed  Google Scholar 

  16. Kryczek I, Wei S, Zhu G, Myers L, Mottram P, Cheng P, Chen L, Coukos G, Zou W (2007) Relationship between B7-H4, regulatory T cells, and patient outcome in human ovarian carcinoma. Cancer Res 67(18):8900–8905. doi:10.1158/0008-5472.CAN-07-1866

    CAS  Article  PubMed  Google Scholar 

  17. Liu W, Shibata K, Koya Y, Kajiyama H, Senga T, Yamashita M, Kikkawa F (2014) B7-H4 overexpression correlates with a poor prognosis for cervical cancer patients. Mol Clin Oncol 2(2):219–225. doi:10.3892/mco.2013.225

    PubMed  Google Scholar 

  18. Chen LJ, Sun J, Wu HY, Zhou SM, Tan Y, Tan M, Shan BE, Lu BF, Zhang XG (2011) B7-H4 expression associates with cancer progression and predicts patient’s survival in human esophageal squamous cell carcinoma. Cancer Immunol Immunother 60(7):1047–1055. doi:10.1007/s00262-011-1017-3

    CAS  Article  PubMed  Google Scholar 

  19. Jiang J, Zhu Y, Wu C, Shen Y, Wei W, Chen L, Zheng X, Sun J, Lu B, Zhang X (2010) Tumor expression of B7-H4 predicts poor survival of patients suffering from gastric cancer. Cancer Immunol Immunother 59(11):1707–1714. doi:10.1007/s00262-010-0900-7

    CAS  Article  PubMed  Google Scholar 

  20. Zhang L, Sun ZJ, Bian Y, Kulkarni AB (2013) MicroRNA-135b acts as a tumor promoter by targeting the hypoxia-inducible factor pathway in genetically defined mouse model of head and neck squamous cell carcinoma. Cancer Lett 331(2):230–238. doi:10.1016/j.canlet.2013.01.003

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 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 

  23. Huang CF, Zhang L, Ma SR, Zhao ZL, Wang WM, He KF, Zhao YF, Zhang WF, Liu B, Sun ZJ (2013) Clinical significance of Keap1 and Nrf2 in oral squamous cell carcinoma. PLoS One 8(12):e83479. doi:10.1371/journal.pone.0083479

    Article  PubMed  PubMed Central  Google Scholar 

  24. Eisen MB, Spellman PT, Brown PO, Botstein D (1998) Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci USA 95(25):14863–14868

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. Saldanha AJ (2004) Java Treeview—extensible visualization of microarray data. Bioinformatics 20(17):3246–3248. doi:10.1093/bioinformatics/bth349

    CAS  Article  PubMed  Google Scholar 

  26. 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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. Serafini P, Borrello I, Bronte V (2006) Myeloid suppressor cells in cancer: recruitment, phenotype, properties, and mechanisms of immune suppression. Semin Cancer Biol 16(1):53–65. doi:10.1016/j.semcancer.2005.07.005

    CAS  Article  PubMed  Google Scholar 

  28. Bian Y, Hall B, Sun ZJ, Molinolo A, Chen W, Gutkind JS, Waes CV, Kulkarni AB (2012) Loss of TGF-beta signaling and PTEN promotes head and neck squamous cell carcinoma through cellular senescence evasion and cancer-related inflammation. Oncogene 31(28):3322–3332. doi:10.1038/onc.2011.494

    CAS  Article  PubMed  Google Scholar 

  29. Quandt D, Fiedler E, Boettcher D, Marsch W, Seliger B (2011) B7-h4 expression in human melanoma: its association with patients’ survival and antitumor immune response. Clin Cancer Res 17(10):3100–3111. doi:10.1158/1078-0432.CCR-10-2268

    CAS  Article  PubMed  Google Scholar 

  30. Krambeck AE, Thompson RH, Dong H, Lohse CM, Park ES, Kuntz SM, Leibovich BC, Blute ML, Cheville JC, Kwon ED (2006) B7-H4 expression in renal cell carcinoma and tumor vasculature: associations with cancer progression and survival. Proc Natl Acad Sci USA 103(27):10391–10396. doi:10.1073/pnas.0600937103

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. Zou W, Chen L (2008) Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol 8(6):467–477. doi:10.1038/nri2326

    CAS  Article  PubMed  Google Scholar 

  32. D’Amato V, Rosa R, D’Amato C, Formisano L, Marciano R, Nappi L, Raimondo L, Di Mauro C, Servetto A, Fusciello C, Veneziani BM, De Placido S, Bianco R (2014) The dual PI3K/mTOR inhibitor PKI-587 enhances sensitivity to cetuximab in EGFR-resistant human head and neck cancer models. Br J Cancer 110(12):2887–2895. doi:10.1038/bjc.2014.241

    Article  PubMed  PubMed Central  Google Scholar 

  33. Parsa AT, Waldron JS, Panner A, Crane CA, Parney IF, Barry JJ, Cachola KE, Murray JC, Tihan T, Jensen MC, Mischel PS, Stokoe D, Pieper RO (2007) Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med 13(1):84–88. doi:10.1038/nm1517

    CAS  Article  PubMed  Google Scholar 

  34. Zhang P, Yu S, Li H, Liu C, Li J, Lin W, Gao A, Wang L, Gao W, Sun Y (2015) ILT4 drives B7-H3 expression via PI3K/AKT/mTOR signalling and ILT4/B7-H3 co-expression correlates with poor prognosis in non-small cell lung cancer. FEBS Lett 589(17):2248–2256. doi:10.1016/j.febslet.2015.06.037

    CAS  Article  PubMed  Google Scholar 

  35. Bian Y, Terse A, Du J, Hall B, Molinolo A, Zhang P, Chen W, Flanders KC, Gutkind JS, Wakefield LM, Kulkarni AB (2009) Progressive tumor formation in mice with conditional deletion of TGF-beta signaling in head and neck epithelia is associated with activation of the PI3K/Akt pathway. Cancer Res 69(14):5918–5926. doi:10.1158/0008-5472.CAN-08-4623

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. Badoual C, Hans S, Merillon N, Van Ryswick C, Ravel P, Benhamouda N, Levionnois E, Nizard M, Si-Mohamed A, Besnier N, Gey A, Rotem-Yehudar R, Pere H, Tran T, Guerin CL, Chauvat A, Dransart E, Alanio C, Albert S, Barry B, Sandoval F, Quintin-Colonna F, Bruneval P, Fridman WH, Lemoine FM, Oudard S, Johannes L, Olive D, Brasnu D, Tartour E (2013) PD-1-expressing tumor-infiltrating T cells are a favorable prognostic biomarker in HPV-associated head and neck cancer. Cancer Res 73(1):128–138. doi:10.1158/0008-5472.CAN-12-2606

    CAS  Article  PubMed  Google Scholar 

  38. Malaspina TS, Gasparoto TH, Costa MR, de Melo EF Jr, Ikoma MR, Damante JH, Cavassani KA, Garlet GP, da Silva JS, Campanelli AP (2011) Enhanced programmed death 1 (PD-1) and PD-1 ligand (PD-L1) expression in patients with actinic cheilitis and oral squamous cell carcinoma. Cancer Immunol Immunother 60(7):965–974. doi:10.1007/s00262-011-1007-5

    CAS  Article  PubMed  Google Scholar 

  39. 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 

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Acknowledgments

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

      Lei Wu, Wei-Wei Deng, Guang-Tao Yu, Liang Mao, Lin-Lin Bu, Si-Rui Ma, Bing Liu, Wen-Feng Zhang & Zhi-Jun Sun

    2. Department of Oral Maxillofacial-Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, 430079, Hubei Province, People’s Republic of China

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

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

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    Wu, L., Deng, WW., Yu, GT. et al. B7-H4 expression indicates poor prognosis of oral squamous cell carcinoma. Cancer Immunol Immunother 65, 1035–1045 (2016). https://doi.org/10.1007/s00262-016-1867-9

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    Keywords

    • B7-H4
    • Immune checkpoint
    • Immunotherapy
    • Oral squamous cell carcinoma
    • Transgenic mice
    • Tissue microarray