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B7-H1 Expression Model for Immune Evasion in Human Papillomavirus-Related Oropharyngeal Squamous Cell Carcinoma

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Abstract

Human papillomavirus (HPV) is associated with oropharyngeal squamous cell carcinomas. Persistent viral infection is postulated to lead to carcinogenesis, although infection of benign adjacent epithelium is not typically observed. It is known that immune evasive tumor cells can provide an ideal niche for a virus. The B7-H1/PD-1 cosignaling pathway plays an important role in viral immune evasion by rendering CD8+ cytotoxic T cells anergic. We hypothesized that HPV-related oropharyngeal squamous cell carcinomas express B7-H1 as a mechanism for immune evasion. A tissue microarray was utilized, for which HPV E6/E7 mRNA by in situ hybridization was previously performed. Immunohistochemistry was performed to detect B7-H1 and staining was characterized by pattern, distribution, and intensity. B7-H1 was expressed by 84 of the 181 (46.4 %) cases. Both tumor cell membranous and cytoplasmic expression were present and cytoplasmic expression was identified in some peritumoral lymphocytes. Expression was analyzed in several different ways and then considered binarily as positive versus negative. Tumors expressing B7-H1 were more likely to be HPV positive (49.2 vs. 34.1 %, p = 0.08). B7-H1 expression showed no correlation with disease recurrence in the entire cohort (OR = 1.09, p = 0.66), HPV positive cohort (OR = 0.80, p = 0.69) or HPV negative cohort (OR = 2.02, p = 0.22). However, B7-H1 expression intensity did correlate with the development of distant metastasis (p = 0.03), and B7-H1 intensity of 3+ (versus all other staining) showed a strong trend towards distant metastasis in the HPV positive (OR = 6.67, p = 0.13) and HPV negative (OR = 9.0, p = 0.13) cohorts. There was no correlation between B7-H1 expression and patient survival for any of the different ways in which staining was characterized, whether binarily, by distribution, intensity, or combined scores. B7-H1 is expressed in the majority of oropharyngeal squamous cell carcinomas with transcriptionally-active HPV. This suggests that B7-H1 expression by tumor cells may play a role in harboring persistent HPV infection.

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References

  1. Adelstein DJ, Ridge JA, Gillison ML, et al. Head and neck squamous cell cancer and the human papillomavirus: summary of a National Cancer Institute State of the Science Meeting, November 9–10, 2008, Washington, DC. Head Neck. 2009;31(11):1393–422.

    Article  PubMed  Google Scholar 

  2. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363(1):24–35.

    Article  PubMed  CAS  Google Scholar 

  3. Gillison ML, Broutian T, Pickard RK, et al. Prevalence of oral HPV infection in the United States, 2009–2010. JAMA. 2012;307(7):693–703.

    Article  PubMed  CAS  Google Scholar 

  4. Gillison ML, Koch WM, Capone RB, et al. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst. 2000;92(9):709–20.

    Article  PubMed  CAS  Google Scholar 

  5. Cerovac Z, Sarcevic B, Kralj Z, Ban J. Detection of human papillomavirus (HPV) type 6, 16 and 18 in head and neck squamous cell carcinomas by in situ hybridization. Neoplasma. 1996;43(3):185–94.

    PubMed  CAS  Google Scholar 

  6. Ritchie JM, Smith EM, Summersgill KF, et al. Human papillomavirus infection as a prognostic factor in carcinomas of the oral cavity and oropharynx. Int J Cancer. 2003;104(3):336–44.

    Article  PubMed  CAS  Google Scholar 

  7. Snow AN, Laudadio J. Human papillomavirus detection in head and neck squamous cell carcinomas. Adv Anat Pathol. 2010;17(6):394–403.

    Article  PubMed  CAS  Google Scholar 

  8. Ukpo OC, Pritchett CV, Lewis JE, Weaver AL, Smith DI, Moore EJ. Human papillomavirus-associated oropharyngeal squamous cell carcinomas: primary tumor burden and survival in surgical patients. Ann Otol Rhinol Laryngol. 2009;118(5):368–73.

    PubMed  Google Scholar 

  9. Duray A, Descamps G, Bettonville M, et al. High prevalence of high-risk human papillomavirus in palatine tonsils from healthy children and adults. Otolaryngol Head Neck Surg. 2011;145(2):230–5.

    Article  PubMed  Google Scholar 

  10. Rice PS, Mant C, Cason J, et al. High prevalence of human papillomavirus type 16 infection among children. J Med Virol. 2000;61(1):70–5.

    Article  PubMed  CAS  Google Scholar 

  11. Rintala M, Grenman S, Puranen M, Syrjanen S. Natural history of oral papillomavirus infections in spouses: a prospective Finnish HPV Family Study. J Clin Virol. 2006;35(1):89–94.

    Article  PubMed  Google Scholar 

  12. Rintala MA, Grenman SE, Jarvenkyla ME, Syrjanen KJ, Syrjanen SM. High-risk types of human papillomavirus (HPV) DNA in oral and genital mucosa of infants during their first 3 years of life: experience from the Finnish HPV Family Study. Clin Infect Dis. 2005;41(12):1728–33.

    Article  PubMed  Google Scholar 

  13. Rintala MA, Grenman SE, Puranen MH, et al. Transmission of high-risk human papillomavirus (HPV) between parents and infant: a prospective study of HPV in families in Finland. J Clin Microbiol. 2005;43(1):376–81.

    Article  PubMed  Google Scholar 

  14. Beachler DC, Weber KM, Margolick JB, et al. Risk factors for oral HPV infection among a high prevalence population of HIV-positive and at-risk HIV-negative adults. Cancer Epidemiol Biomarkers Prev. 2012;21(1):122–33.

    Article  PubMed  CAS  Google Scholar 

  15. Kreuter A, Wieland U. Human papillomavirus-associated diseases in HIV-infected men who have sex with men. Curr Opin Infect Dis. 2009;22(2):109–14.

    Article  PubMed  Google Scholar 

  16. Begum S, Gillison ML, Nicol TL, Westra WH. Detection of human papillomavirus-16 in fine-needle aspirates to determine tumor origin in patients with metastatic squamous cell carcinoma of the head and neck. Clin Cancer Res. 2007;13(4):1186–91.

    Article  PubMed  CAS  Google Scholar 

  17. Tamura H, Ogata K, Dong H, Chen L. Immunology of B7-H1 and its roles in human diseases. Int J Hematol. 2003;78(4):321–8.

    Article  PubMed  CAS  Google Scholar 

  18. Barber DL, Wherry EJ, Masopust D, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006;439(7077):682–7.

    Article  PubMed  CAS  Google Scholar 

  19. Blank C, Kuball J, Voelkl S, et al. Blockade of PD-L1 (B7–H1) augments human tumor-specific T cell responses in vitro. Int J Cancer. 2006;119(2):317–27.

    Article  PubMed  CAS  Google Scholar 

  20. Blank C, Mackensen A. Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: an update on implications for chronic infections and tumor evasion. Cancer Immunol Immunother. 2007;56(5):739–45.

    Article  PubMed  Google Scholar 

  21. Cao Y, Zhang L, Kamimura Y, et al. B7–H1 overexpression regulates epithelial-mesenchymal transition and accelerates carcinogenesis in skin. Cancer Res. 2011;71(4):1235–43.

    Article  PubMed  CAS  Google Scholar 

  22. Cao Y, Zhang L, Ritprajak P, et al. Immunoregulatory molecule B7-H1 (CD274) contributes to skin carcinogenesis. Cancer Res. 2011;71(14):4737–41.

    Article  PubMed  CAS  Google Scholar 

  23. Chen J, Li G, Meng H, et al. Upregulation of B7-H1 expression is associated with macrophage infiltration in hepatocellular carcinomas. Cancer Immunol Immunother. 2012;61(1):101–8.

    Article  PubMed  Google Scholar 

  24. Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8(8):793–800.

    PubMed  CAS  Google Scholar 

  25. Gadiot J, Hooijkaas AI, Kaiser AD, van Tinteren H, van Boven H, Blank C. Overall survival and PD-L1 expression in metastasized malignant melanoma. Cancer. 2011;117(10):2192–201.

    Article  PubMed  CAS  Google Scholar 

  26. Konishi J, Yamazaki K, Azuma M, Kinoshita I, Dosaka-Akita H, Nishimura M. B7-H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression. Clin Cancer Res. 2004;10(15):5094–100.

    Article  PubMed  CAS  Google Scholar 

  27. Lu B, Chen L, Liu L, et al. T-cell-mediated tumor immune surveillance and expression of B7 co-inhibitory molecules in cancers of the upper gastrointestinal tract. Immunol Res. 2011;50(2–3):269–75.

    Article  PubMed  CAS  Google Scholar 

  28. Thompson RH, Gillett MD, Cheville JC, et al. Costimulatory B7-H1 in renal cell carcinoma patients: indicator of tumor aggressiveness and potential therapeutic target. Proc Natl Acad Sci USA. 2004;101(49):17174–9.

    Article  PubMed  CAS  Google Scholar 

  29. Wang L, Ma Q, Chen X, Guo K, Li J, Zhang M. Clinical significance of B7-H1 and B7-1 expressions in pancreatic carcinoma. World J Surg. 2010;34(5):1059–65.

    Article  PubMed  Google Scholar 

  30. Ukpo OC, Flanagan JJ, Ma XJ, Luo Y, Thorstad WL, Lewis JS Jr. High-risk human papillomavirus E6/E7 mRNA detection by a novel in situ hybridization assay strongly correlates with p16 expression and patient outcomes in oropharyngeal squamous cell carcinoma. Am J Surg Pathol. 2011;35(9):1343–50.

    Article  PubMed  Google Scholar 

  31. Turner DO, Williams-Cocks SJ, Bullen R, et al. High-risk human papillomavirus (HPV) screening and detection in healthy patient saliva samples: a pilot study. BMC Oral Health. 2011;11:28.

    Article  PubMed  Google Scholar 

  32. Malaspina TS, Gasparoto TH, Costa MR, et al. 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. 2011;60(7):965–74.

    Article  PubMed  CAS  Google Scholar 

  33. Cho YA, Yoon HJ, Lee JI, Hong SP, Hong SD. Relationship between the expressions of PD-L1 and tumor-infiltrating lymphocytes in oral squamous cell carcinoma. Oral Oncol. 2011;47(12):1148–53.

    Article  PubMed  CAS  Google Scholar 

  34. Karim R, Jordanova ES, Piersma SJ, et al. Tumor-expressed B7–H1 and B7-DC in relation to PD-1+ T-cell infiltration and survival of patients with cervical carcinoma. Clin Cancer Res. 2009;15(20):6341–7.

    Article  PubMed  CAS  Google Scholar 

  35. Chernock RD, El-Mofty SK, Thorstad WL, Parvin CA, Lewis JS Jr. HPV-related nonkeratinizing squamous cell carcinoma of the oropharynx: utility of microscopic features in predicting patient outcome. Head Neck Pathol. 2009;3(3):186–94.

    Article  PubMed  Google Scholar 

  36. Lewis JS Jr, Thorstad WL, Chernock RD, et al. p16 positive oropharyngeal squamous cell carcinoma:an entity with a favorable prognosis regardless of tumor HPV status. Am J Surg Pathol. 2011;34(8):1088–96.

    Article  Google Scholar 

  37. Weinberger PM, Yu Z, Haffty BG, et al. Molecular classification identifies a subset of human papillomavirus–associated oropharyngeal cancers with favorable prognosis. J Clin Oncol. 2006;24(5):736–47.

    Article  PubMed  CAS  Google Scholar 

  38. Hannisdal K, Schjolberg A, De Angelis PM, Boysen M, Clausen OP. Human papillomavirus (HPV)-positive tonsillar carcinomas are frequent and have a favourable prognosis in males in Norway. Acta Otolaryngol. 2010;130(2):293–9.

    Article  PubMed  CAS  Google Scholar 

  39. D’Souza G, Zhang HH, D’Souza WD, Meyer RR, Gillison ML. Moderate predictive value of demographic and behavioral characteristics for a diagnosis of HPV16-positive and HPV16-negative head and neck cancer. Oral Oncol. 2010;46(2):100–4.

    Article  PubMed  Google Scholar 

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Acknowledgments

We would like to acknowledge Xiao-Jun Ma PhD and Yuling Luo PhD from Advanced Cell Diagnostics, Inc. for the prior RNAscope™ in situ hybridization studies that were performed on the tissue microarray cohort for a previous study. We would also like to acknowledge Haidong Dong MD, PhD for providing the B7-H1 immunostaining on this study.

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Authors and Affiliations

  1. Department of Pathology and Immunology, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8118, St. Louis, MO, 63110, USA

    Odey C. Ukpo & James S. Lewis Jr.

  2. Department of Radiation Oncology, Washington University, St. Louis, MO, USA

    Wade L. Thorstad

  3. Department of Otolaryngology Head and Neck Surgery, Washington University, St. Louis, MO, USA

    James S. Lewis Jr.

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  1. Odey C. Ukpo
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  2. Wade L. Thorstad
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Correspondence to James S. Lewis Jr..

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Ukpo, O.C., Thorstad, W.L. & Lewis, J.S. B7-H1 Expression Model for Immune Evasion in Human Papillomavirus-Related Oropharyngeal Squamous Cell Carcinoma. Head and Neck Pathol 7, 113–121 (2013). https://doi.org/10.1007/s12105-012-0406-z

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  • DOI: https://doi.org/10.1007/s12105-012-0406-z

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