The Role of Immune Modulation in the Carcinogenesis and Treatment of HPV-Associated Oropharyngeal Cancer

  • Nicole C. Schmitt
  • Robert L. Ferris
  • Seungwon KimEmail author


Human papillomavirus (HPV) is increasingly identified as a causative agent for oropharyngeal squamous cell carcinoma (OPSCC), often in relatively young patients lacking traditional carcinogenic risk factors such as tobacco and alcohol use. A growing body of literature has highlighted the importance of immune impairment in the pathogenesis of HPV-related premalignant and malignant lesions in the uterine cervix and, more recently, the oropharynx. This chapter will summarize current knowledge of the mechanisms that human papillomaviruses have evolved to evade the host immune system in the development of malignancy and will conclude with a discussion on preventive and therapeutic strategies that exploit these immune modulatory mechanisms.


Natural Killer Cell Oropharyngeal Squamous Cell Carcinoma Tonsillar Crypt Immune Checkpoint Pathway 
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  1. Albers A, Abe K, Hunt J et al (2005) Antitumor activity of human papillomavirus type 16 E7-specific T cells against virally infected squamous cell carcinoma of the head and neck. Cancer Res 65:11146–11154PubMedCrossRefGoogle Scholar
  2. Alcocer-Gonzalez JM, Berumen J, Taméz-Guerra R et al (2006) In vivo expression of immunosuppressive cytokines in human papillomavirus-transformed cervical cancer cells. Viral Immunol 19:481–491PubMedCrossRefGoogle Scholar
  3. Allen C, Lewis J, El-Mofty S et al (2010) Human papillomavirus and oropharynx cancer: biology, detection and clinical implications. Laryngoscope 120:1756–1772PubMedCrossRefGoogle Scholar
  4. Allen C, Judd N, Bui J et al (2011) The clinical implications of antitumor immunity in head and neck cancer. Laryngoscope 122:144–157CrossRefGoogle Scholar
  5. Badoual C, Hans S, Merillon N et al (2013) PD-1-expressing tumor infiltrating T cells are a favorable prognostic biomarker in HPV-associated head and neck cancer. Cancer Res 73:128–138PubMedCrossRefGoogle Scholar
  6. Bauman JE, Gooding WE, Clump DA et al (2014) Phase I trial of cetuximab, intensity modulated radiotherapy (IMRT), and the anti-CTLA-4 monoclonal antibody (mAb) ipilimumab in previously untreated, locally advanced head and neck squamous cell carcinoma (PULA HNSCC). Abstracts from the annual meeting of the American Society of Clinical Oncology, Chicago, Illinois, 31 May–3 June, 2014Google Scholar
  7. Beachler DC, Weber KM, Margolick JB et al (2012) Risk factors for oral HPV infection among a high prevalence population of HIV-positive and at-risk HIV-negative adults. Cancer Epidemiol Biomarkers Prev 21:122–133PubMedCentralPubMedCrossRefGoogle Scholar
  8. Best S, Niparko K, Pai S (2012) Biology of human papillomavirus infection and immune therapy for HPV-related head and neck cancers. Otolaryngol Clin N Am 45:807–822CrossRefGoogle Scholar
  9. Bhat P, Mattarollo SR, Gosmann C et al (2011) Regulation of immune responses to HPV infection and during HPV-directed immunotherapy. Immunol Rev 239:85–98PubMedCrossRefGoogle Scholar
  10. Bodily J, Laimins LA (2011) Persistence of human papillomavirus infection: keys to malignant progression. Trends Microbiol 19:33–39PubMedCentralPubMedCrossRefGoogle Scholar
  11. Brun JL, Dalstein V, Leveque J et al (2011) Regression of high-grade cervical intraepithelial neoplasia with TG4001 targeted immunotherapy. Am J Obstet Gynecol 204:169.e1–8Google Scholar
  12. Chang YE, Laimins LA (2000) Microarray analysis identifies interferon-inducible genes and Stat-1 as major transcriptional targets of human papillomavirus type 31. J Virol 74:4174–4182PubMedCentralPubMedCrossRefGoogle Scholar
  13. Clinical Trials Database (2014) National Cancer Institute, Bethesda. Accessed 26 June 2014
  14. Denny LA, Franceschi S, de Sanjosé S et al (2012) Human papillomavirus, human immunodeficiency virus and immunosuppression. Vaccine 30S:F168–F174CrossRefGoogle Scholar
  15. Duray A, Demoulin S, Hubert P et al (2010) Immune suppression in head and neck cancers: a review. Clin Dev Immunol 2010:701657PubMedCentralPubMedCrossRefGoogle Scholar
  16. El-Omar EM, Ng MT, Hold GL (2008) Polymorphisms in toll-like receptor genes and risk of cancer. Oncogene 27:244–252PubMedCrossRefGoogle Scholar
  17. Ferris R (2013) PD-1 targeting in cancer immunotherapy. Cancer 119. doi: 10.1002/cncr.27832
  18. Frazer IH (2009) Interaction of human papillomaviruses with the host immune system: a well evolved relationship. Virology 384:410–414PubMedCrossRefGoogle Scholar
  19. Gildener-Leapman N, Lee J, Ferris RL (2013) Tailored immunotherapy for HPV positive head and neck squamous cell cancer. Oral Oncol. doi: 10.1038/bjc.2013.645 PubMedCentralGoogle Scholar
  20. Giuliano AR, Palefsky JM, Goldstone S et al (2011) Efficacy of quadrivalent HPV vaccine against HPV infection and disease in males. N Engl J Med 364:401–411PubMedCentralPubMedCrossRefGoogle Scholar
  21. Kanodia S, Fahey LM, Kast WM (2007) Mechanisms used by human papillomaviruses to escape the host immune response. Curr Cancer Drug Targets 7:79–89PubMedCrossRefGoogle Scholar
  22. King EV, Ottensmeier CH, Thomas GJ (2014) The immune response in HPV+ oropharyngeal cancer. Oncoimmunol 3:e27254CrossRefGoogle Scholar
  23. Koskinen WJ, Partanen J, Vaheri A et al (2006) HLA-DRB1, -DQB1 alleles in head and neck carcinoma patients. Tissue Antigens 67:237–240PubMedCrossRefGoogle Scholar
  24. Lyford-Pike S, Peng S, Young G et al (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 73:1733–1741PubMedCentralPubMedCrossRefGoogle Scholar
  25. Madkan VK, Cook-Norris RH, Steadman MC et al (2007) The oncogenic potential of human papillomaviruses: a review on the role of host genetics and environmental factors. Br J Dermatol 157:228–241PubMedCrossRefGoogle Scholar
  26. Malejczyk J, Malejczyk M, Majewski S et al (1994) Increased tumorigenicity of human keratinocytes harboring human papillomavirus type 16 is associated with resistance to endogenous tumor necrosis factor-alpha-mediated growth limitation. Int J Cancer 56:593–598PubMedCrossRefGoogle Scholar
  27. Malm IJ, Bruno TC, Fu J et al (2014) Expression profile and in vitro blockade of PD-1 in HPV-negative head and neck squamous cell carcinoma. Head Neck. doi: 10.1002/hed.23706 PubMedGoogle Scholar
  28. Näsman A, Romanitan M, Nordfors C et al (2012) Tumor Infiltrating CD8+ and Foxp3+ lymphocytes correlate to clinical outcome and human papillomavirus (HPV) status in tonsillar cancer. PLoS ONE 7:e38711PubMedCentralPubMedCrossRefGoogle Scholar
  29. Nees M, Geoghegan JM, Hyman T et al (2001) Papillomavirus type 16 oncogenes downregulate expression of interferon-responsive genes and upregulate proliferation-associated and NF-kB-responsive genes in cervical keratinocytes. J Virol 75:4283–4296PubMedCentralPubMedCrossRefGoogle Scholar
  30. O’Brien PM, Campo MS (2002) Evasion of host immunity directed by human papillomavirus-encoded proteins. Virus Res 88:103–117PubMedCrossRefGoogle Scholar
  31. Pai S (2013) Adaptive immune resistance in HPV-associated head and neck squamous cell carcinoma. Oncoimmunol 2:e24065CrossRefGoogle Scholar
  32. Quezada S, Peggs K (2013) Exploiting CTLA-4, PD-1 and PD-L1 to reactivate the host immune response against cancer. Br J Cancer 108:1560–1565PubMedCentralPubMedCrossRefGoogle Scholar
  33. Schiller JT, Castellsagué X, Garland SM (2012) A review of clinical trials of human papillomavirus prophylactic vaccines. Vaccine 30S:F123–F138CrossRefGoogle Scholar
  34. Scott M, Nakagawa M, Moscicki A (2001) Cell-mediated immune response to human papillomavirus infection. Clin Diagn Lab Immunol 8:209–220PubMedCentralPubMedGoogle Scholar
  35. Sewell DA, Pan ZK, Paterson Y (2008) Listeria-based HPV-16 E7 vaccines limit autochthonous tumor growth in a transgenic mouse model for HPV-16 transformed tumors. Vaccine 26:5315–5320PubMedCentralPubMedCrossRefGoogle Scholar
  36. Sin JI, Kim JM, Bae SH et al (2009) Adoptive transfer of human papillomavirus E7-specific CTL enhances tumor chemoresponse through the perforin-/granzyme-mediated pathway. Mol Ther 17:906–913PubMedCentralPubMedCrossRefGoogle Scholar
  37. Spanos WC, Nowicki P, Lee DW et al (2009) Immune response during therapy with cisplatin or radiation for human papillomavirus-related head and neck cancer. Arch Otolaryngol Head Neck Surg 135:1137–1146 PubMedCrossRefGoogle Scholar
  38. Stanley MA, Pett MR, Coleman N (2007) HPV: from infection to cancer. Biochem Soc Trans 35:1456–1460PubMedCrossRefGoogle Scholar
  39. Stanley MA (2008) Immunobiology of HPV and HPV vaccines. Gyn Oncol 109:S15–S21CrossRefGoogle Scholar
  40. Stanley MA, Pinto LA, Trimble C (2012) Human papillomavirus vaccines—immune response. Vaccine 30S:F83–F87CrossRefGoogle Scholar
  41. Tindle RW (2002) Immune evasion in human papillomavirus-associated cervical cancer. Cancer 2:1–7Google Scholar
  42. Vambutas A, DeVoti J, Pinn W et al (2001) Interaction of human papillomavirus type 11 E7 protein with TAP-1 results in the reduction of ATP-dependent peptide transport. Clin Immunol 101:94–99PubMedCrossRefGoogle Scholar
  43. Vu HL, Sikora AG, Fu S et al (2010) HPV-induced oropharyngeal cancer, immune response and response to therapy. Cancer Lett 288:149–155PubMedCrossRefGoogle Scholar
  44. Zhou Q, Zhu K, Cheng H (2011) Ubiquitination in host immune responses to human papillomavirus infection. Arch Dermatol Res 303:217–230PubMedCrossRefGoogle Scholar
  45. Zhou Q, Zhu K, Cheng H (2013) Toll-like receptors in human papillomavirus infection. Arch Immunol Ther Exp 61:203–215CrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Nicole C. Schmitt
    • 1
  • Robert L. Ferris
    • 1
  • Seungwon Kim
    • 1
    Email author
  1. 1.Department of OtolaryngologyEye & Ear Institute, University of PittsburghPittsburghUSA

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