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Immune responses against human papillomavirus (HPV) infection and evasion of host defense in cervical cancer

Abstract

Human papillomavirus (HPV) is the most important etiological factor for cervical cancer. A recent study demonstrated that more than 20 HPV types were thought to be oncogenic for uterine cervical cancer. Notably, more than one-half of women show cervical HPV infections soon after their sexual debut, and about 90 % of such infections are cleared within 3 years. Immunity against HPV might be important for elimination of the virus. The innate immune responses involving macrophages, natural killer cells, and natural killer T cells may play a role in the first line of defense against HPV infection. In the second line of defense, adaptive immunity via cytotoxic T lymphocytes (CTLs) targeting HPV16 E2 and E6 proteins appears to eliminate cells infected with HPV16. However, HPV can evade host immune responses. First, HPV does not kill host cells during viral replication and therefore neither presents viral antigen nor induces inflammation. HPV16 E6 and E7 proteins downregulate the expression of type-1 interferons (IFNs) in host cells. The lack of co-stimulatory signals by inflammatory cytokines including IFNs during antigen recognition may induce immune tolerance rather than the appropriate responses. Moreover, HPV16 E5 protein downregulates the expression of HLA-class 1, and it facilitates evasion of CTL attack. These mechanisms of immune evasion may eventually support the establishment of persistent HPV infection, leading to the induction of cervical cancer. Considering such immunological events, prophylactic HPV16 and 18 vaccine appears to be the best way to prevent cervical cancer in women who are immunized in adolescence.

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References

  1. zur Hausen H. Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer. 2002;2:342–50.

    PubMed  Article  CAS  Google Scholar 

  2. Shigehara K, Sasagawa T, Kawaguchi S, Nakashima T, Shimamura M, Maeda Y, et al. Etiologic role of human papillomavirus infection in bladder carcinoma. Cancer. 2011;117:2067–76.

    PubMed  Article  CAS  Google Scholar 

  3. Bernard HU, Burk RD, Chen Z, van Doorslaer K, Hausen H, de Villiers EM. Classification of papillomaviruses (PVs) based on 189 PV types and proposal of taxonomic amendments. Virology. 2010;401:70–9.

    PubMed  Article  CAS  Google Scholar 

  4. Muñoz N, Bosch FX, de Sanjosé S, Herrero R, Castellsagué X, Shah KV, Snijders PJ, Meijer CJ. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med. 2003;348:518–27.

    PubMed  Article  Google Scholar 

  5. de Sanjose S, Quint WG, Alemany L, Geraets DT, Klaustermeier JE, Lloveras B, et al. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncol. 2010;11:1048–56.

    PubMed  Article  Google Scholar 

  6. Matsukura T, Sugase M. Human papillomavirus genomes in squamous cell carcinomas of the uterine cervix. Virology. 2004;324:439–49.

    PubMed  Article  CAS  Google Scholar 

  7. Sasagawa T, Basha W, Yamazaki H, Inoue M. High-risk and multiple human papillomavirus infections associated with cervical abnormalities in Japanese women. Cancer Epidemiol Biomarkers Prev. 2001;10:45–52.

    PubMed  CAS  Google Scholar 

  8. Doorbar J. Molecular biology of human papillomavirus infection and cervical cancer. Clin Sci (Lond). 2006;110:525–41.

    Article  CAS  Google Scholar 

  9. Moscicki AB. Impact of HPV infection in adolescent populations. J Adolesc Health. 2005;37:S3–9 (review).

    Google Scholar 

  10. Gadducci A, Barsotti C, Cosio S, Domenici L, Riccardo Genazzani A. Smoking habit, immune suppression, oral contraceptive use, and hormone replacement therapy use and cervical carcinogenesis: a review of the literature. Gynecol Endocrinol. 2011;27:597–604.

    PubMed  Article  Google Scholar 

  11. Stanley MA. Immune responses to human papilloma viruses. Indian J Med Res. 2009;130:266–76.

    PubMed  CAS  Google Scholar 

  12. Palefsky J. Human papillomavirus-associated malignancies in HIV-positive men and women. Curr Opin Oncol. 1995;7:437–41.

    PubMed  Article  CAS  Google Scholar 

  13. de Jong A, van der Burg SH, Kwappenberg KM, van der Hulst JM, Franken KL, Geluk A, et al. Frequent detection of human papillomavirus 16 E2-specific T-helper immunity in healthy subjects. Cancer Res. 2002;62:472–509.

    PubMed  Google Scholar 

  14. Welters MJ, de Jong A, van den Eeden SJ, van der Hulst JM, Kwappenberg KM, Hassane S, et al. Frequent display of human papillomavirus type 16 E6-specific memory T-helper cells in the healthy population as witness of previous viral encounter. Cancer Res. 2003;63:636–41.

    PubMed  CAS  Google Scholar 

  15. Welters MJP, van der Logt P, van den Eeden SJF, Kwapenberg KMC, Drijfhout JW, Fleuren GJ, et al. Detection of human papillomavirus type 18 E6 and E7-specific CD4+ T-helper 1 immunity in relation to health versus disease. Int J Cancer. 2006;118:950–6.

    PubMed  Article  CAS  Google Scholar 

  16. Yamada R, Sasagawa T, Kirumbi LW, Kingoro A, Karanja DK, Kiptoo M, Nakitare GW, Ichimura H, Inoue M. Human papillomavirus infection and cervical abnormalities in Nairobi, Kenya, an area with a high prevalence of human immunodeficiency virus infection. J Med Virol. 2008;80:847–55.

    PubMed  Article  CAS  Google Scholar 

  17. Rahman M, Sasagawa T, Yamada R, Kingoro A, Ichimura H, Makinoda S. High prevalence of intermediate-risk human papillomavirus infection in uterine cervices of Kenyan women infected with human immunodeficiency virus. J Med Virol. 2011;83:1988–96.

    PubMed  Article  Google Scholar 

  18. Grandvaux N, tenOever BR, Servant MJ, Hiscott J. The interferon antiviral response: from viral invasion to evasion. Curr Opin Infect Dis. 2002;15:259–67.

    PubMed  Article  CAS  Google Scholar 

  19. Koromilas AE, Li S, Matlashewski G. Control of interferon signaling in human papillomavirus infection. Cytokine Growth Factor Rev. 2001;12:157–70.

    PubMed  Article  CAS  Google Scholar 

  20. Rincon-Orozco B, Halec G, Rosenberger S, Muschik D, Nindl I, Bachmann A, Ritter TM, Dondog B, Ly R, Bosch FX, Zawatzky R, Rösl F. Epigenetic silencing of interferon-kappa in human papillomavirus type 16-positive cells. Cancer Res. 2009;69:8718–25.

    PubMed  Article  CAS  Google Scholar 

  21. Routes JM, Morris K, Ellison MC, Ryan S. Macrophages kill human papillomavirus type 16 E6-expressing tumor cells by tumor necrosis factor alpha- and nitric oxide-dependent mechanisms. J Virol. 2005;79:116–23.

    PubMed  Article  CAS  Google Scholar 

  22. Hacke K, Rincon-Orozco B, Buchwalter G, Siehler SY, Wasylyk B, Wiesmüller L, Rösl F. Regulation of MCP-1 chemokine transcription by p53. Mol Cancer. 2010;9:82–94.

    PubMed  Article  Google Scholar 

  23. Guess JC, McCance DJ. Decreased migration of Langerhans precursor-like cells in response to human keratinocytes expressing human papillomavirus type 16 E6/E7 is related to reduced macrophage inflammatory protein-3alpha production. J Virol. 2005;79:14852–62.

    PubMed  Article  CAS  Google Scholar 

  24. Laffort C, Le Deist F, Favre M, Caillat-Zucman S, Radford-Weiss J, Debre M, et al. Severe cutaneous papillomavirus disease after haematopoietic stem-cell transplantation in patients with severe combined immune deficiency caused by common gammac cytokine receptor subunit or JAK-3 deficiency. Lancet. 2004;363:2051–4.

    PubMed  Article  CAS  Google Scholar 

  25. Garcia-Iglesias T, Del Toro-Arreola A, Albarran-Somoza B, Del Toro-Arreola S, Sanchez-Hernandez PE, Ramirez-Dueñas MG, et al. Low NKp30, NKp46 and NKG2D expression and reduced cytotoxic activity on NK cells in cervical cancer and precursor lesions. BMC Cancer. 2009;9:186–94.

    PubMed  Article  Google Scholar 

  26. Miura S, Kawana K, Schust DJ, Fujii T, Yokoyama T, Iwasawa Y, Nagamatsu T, Adachi K, Tomio A, Tomio K, Kojima S, Yasugi T, Kozuma S, Taketani Y. CD1d, a sentinel molecule bridging innate and adaptive immunity, is downregulated by the human papillomavirus (HPV) E5 protein: a possible mechanism for immune evasion by HPV. J Virol. 2010;84(22):11614–23.

    PubMed  Article  CAS  Google Scholar 

  27. Fausch SC, Fahey LM, Da Silva DM, Kast WM. Human papillomavirus can escape immune recognition through Langerhans cell phosphoinositide 3-kinase activation. J Immunol. 2005;174:7172–8.

    PubMed  CAS  Google Scholar 

  28. Leong CM, Doorbar J, Nindl I, Yoon HS, Hibma MH. Deregulation of E-cadherin by human papillomavirus is not confined to high-risk, cancer-causing types. Br J Dermatol. 2010;163:1253–63.

    PubMed  Article  Google Scholar 

  29. Nakagawa M, Stites DP, Farhat S, Sisler JR, Moss B, Kong F, Moscicki AB, Palefsky JM. Cytotoxic T lymphocyte responses to E6 and E7 proteins of human papillomavirus type 16: relationship to cervical intraepithelial neoplasia. J Infect Dis. 1997;175:927–31.

    PubMed  Article  CAS  Google Scholar 

  30. Dillon S, Sasagawa T, Crawford A, Prestidge J, Inder MK, Jerram J, et al. Resolution of cervical dysplasia is associated with T-cell proliferative responses to human papillomavirus type 16 E2. J Gen Virol. 2007;88:803–13.

    PubMed  Article  CAS  Google Scholar 

  31. Nakagawa M, Gupta SK, Coleman HN, Sellers MA, Banken JA, Greenfield WW. A favorable clinical trend is associated with CD8 T-cell immune responses to the human papillomavirus type 16 e6 antigens in women being studied for abnormal pap smear results. J Low Genit Tract Dis. 2010;14:124–9.

    PubMed  Article  Google Scholar 

  32. Campo MS, Graham SV, Cortese MS, Ashrafi GH, Araibi EH, Dornan ES, Miners K, Nunes C, Man S. HPV-16 E5 down-regulates expression of surface HLA class I and reduces recognition by CD8 T cells. Virology. 2010;407(1):137–42.

    PubMed  Article  CAS  Google Scholar 

  33. Tindle RW. Immune evasion in human papillomavirus associated cancer. Nat Rev Cancer. 2002;2:59–65.

    PubMed  Article  CAS  Google Scholar 

  34. Azar KK, Yasuda H, Tani M, Basha W, Sakai A, Inoue M, Sasagawa T. Increased secretion patterns of interleukin-10 and tumor necrosis factor-alpha in cervical squamous intraepithelial lesions. Hum Pathol. 2004;35:1376–84.

    PubMed  Article  CAS  Google Scholar 

  35. Nakamura T, Shima T, Saeki A, Hidaka T, Nakashima A, Takikawa O, et al. Expression of indoleamine 2, 3-dioxygenase and the recruitment of Foxp3-expressing regulatory T cells in the development and progression of uterine cervical cancer. Cancer Sci. 2007;98:874–81.

    PubMed  Article  CAS  Google Scholar 

  36. Daayana S, Elkord E, Winters U, Pawlita M, Roden R, Stern PL, et al. Phase II trial of imiquimod and HPV therapeutic vaccination in patients with vulval intraepithelial neoplasia. Br J Cancer. 2010;102:1129–36.

    PubMed  Article  CAS  Google Scholar 

  37. Sasagawa T, Inoue M, Yutsudo M, Tanizawa O, Hakura A. Identification of antibodies against HPV 16 E6 and E7 proteins in the sera of patient with cervical neoplasia. Jpn J Cancer Res. 1992;83:705–13.

    PubMed  Article  CAS  Google Scholar 

  38. Sasagawa T, Yamazaki H, Dong YZ, Satake S, Tateno M, Inoue M. Immunoglobulin-A and -G responses against virus-like particles (VLP) of human papillomavirus type 16 in women with cervical cancer and cervical intraepithelial lesions. Int J Cancer. 1998;75:529–35.

    PubMed  Article  CAS  Google Scholar 

  39. Sasagawa T, Rose RC, Azar KK, Sakai A, Inoue M. Mucosal immunoglobulin-A and -G responses to oncogenic human papilloma virus capsids. Int J Cancer. 2003;104:328–35.

    PubMed  Article  CAS  Google Scholar 

  40. Tiggelaar SM, Lin MJ, Viscidi RP, Ji J, Smith JS. Age-specific human papillomavirus antibody and deoxyribonucleic acid prevalence: a global review. J Adolesc Health. 2012;50:110–31.

    PubMed  Article  Google Scholar 

  41. Kim S, Arduino JM, Roberts CC, Marsico M, Liaw KL, Skjeldestad FE. Incidence and predictors of human papillomavirus-6, -11, -16, and -18 infection in young Norwegian women. Sex Transm Dis. 2011;38:587–97.

    PubMed  Article  Google Scholar 

  42. Brotherton JM, Fridman M, May CL, Chappell G, Saville AM, Gertig DM. Early effect of the HPV vaccination programme on cervical abnormalities in Victoria, Australia: an ecological study. Lancet. 2011;377:2085–92.

    PubMed  Article  Google Scholar 

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Correspondence to Toshiyuki Sasagawa.

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Sasagawa, T., Takagi, H. & Makinoda, S. Immune responses against human papillomavirus (HPV) infection and evasion of host defense in cervical cancer. J Infect Chemother 18, 807–815 (2012). https://doi.org/10.1007/s10156-012-0485-5

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  • DOI: https://doi.org/10.1007/s10156-012-0485-5

Keywords

  • Human papillomavirus
  • Cervical cancer
  • Innate immunity
  • Adaptive immunity
  • Immune evasion
  • Immune tolerance