Immunological Role of Dendritic Cells in Cervical Cancer

  • Alagar Manickam
  • Muthukumaran Sivanandham
  • Irina L. Tourkova
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 601)


Cervical cancer is the second most frequent gynecological malignancy in the world. Human papillomavirus (HPV) infection is the primary etiologic agent of cervical cancer. However, HPV alone is not sufficient for tumor progression. The clinical manifestation of HPV infection depends also on the host’s immune status. Both innate and adaptive immunity play a role in controlling HPV infection. In untransformed HPV-infected keratinocytes, the innate immunity is induced to eliminate the invading HPV pathogen through sensitization to HPV-related proteins by epithelial-residing Langerhans cells (LCs), macrophages, and other immune cells. Once the HPV infection escapes from initial patrolling by innate immunity, cellular immunity becomes in charge of killing the HPV-infected keratinocytes of the uterine cervix through systemic immune response developing by dendritic cells (DCs) in the regional lymphoid organs or through local immune response developing by LCs in the cervix. Thereby, DC/LC plays a critical role in eliciting innate and adaptive cellular immune responses against HPV infection. HPV-associated cervical malignancies might be prevented or treated by induction of the appropriate virus-specific immune responses in patients. Encouraging results from experimental vaccination systems in animal models have led to several prophylactic and therapeutic vaccine clinical trials.


Cervical Cancer Cervical Intraepithelial Neoplasia Uterine Cervix Cervical Cancer Patient Systemic Immune Response 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. Adams, M., Borysiewicz, L., Fiander, A., Man, S., Jasani, B., Navabi, H., Lipetz, C., Evans, A. S. and Mason, M. (2001) Clinical studies of human papilloma vaccines in pre-invasive and invasive cancer. Vaccine 19, 2549–2556.CrossRefPubMedGoogle Scholar
  2. Adams, M., Navabi, H., Jasani, B., Man, S., Fiander, A., Evans, A. S., Donninger, C. and Mason, M. (2003) Dendritic cell (DC) based therapy for cervical cancer: use of DC pulsed with tumour lysate and matured with a novel synthetic clinically non-toxic double stranded RNA analogue poly [I]:poly [C(12)U] (Ampligen R). Vaccine 21, 787–790.CrossRefPubMedGoogle Scholar
  3. Aiba, S. and Katz, S. I. (1990) Phenotypic and functional characteristics of in vivo-activated Langerhans cells. J. Immunol. 145, 2791–2796.PubMedGoogle Scholar
  4. Banchereau, J., Briere, F., Caux, C., Davoust, J., Lebecque, S., Liu, Y. J., Pulendran, B. and Palucka, K. (2000) Immunobiology of dendritic cells. Annu. Rev. Immunol. 18, 767–811.CrossRefPubMedGoogle Scholar
  5. Barberis, M. C., Vago, L., Cecchini, G., Bramerio, M., Banfi, G., D’Amico, M. and Cannone, M. (1998) Local impairment of immunoreactivity in HIV-infected women with HPV-related squamous intraepithelial lesions of the cervix. Tumori 84, 489–492.PubMedGoogle Scholar
  6. Biragyn, A. and Kwak, L. W. (2000) Designer cancer vaccines are still in fashion. Nat. Med. 6, 966–968.CrossRefPubMedGoogle Scholar
  7. Bonilla-Musoles, F., Castells, A., Simon, C., Serra, V., Pellicer, A., Ramirez, A. and Pardo, G. (1987) Importance of Langerhans cells in the immune origin of carcinoma of the uterine cervix. Eur. J. Gynaecol. Oncol. 8, 44–60.PubMedGoogle Scholar
  8. Borkowski, T. A., Van Dyke, B. J., Schwarzenberger, K., McFarland, V. W., Farr, A. G. and Udey, M. C. (1994) Expression of E-cadherin by murine dendritic cells: E-cadherin as a dendritic cell differentiation antigen characteristic of epidermal Langerhans cells and related cells. Eur. J. Immunol. 24, 2767–2774.CrossRefPubMedGoogle Scholar
  9. Caorsi, I. and Figueroa, C. D. (1986) Langerhans’ cell density in the normal exocervical epithelium and in the cervical intraepithelial neoplasia. Br. J. Obstet. Gynaecol. 93, 993–998.PubMedGoogle Scholar
  10. Caux, C., Vanbervliet, B., Massacrier, C., Ait-Yahia, S., Vaure, C., Chemin, K., Dieu, N., Mc and Vicari, A. (2002) Regulation of dendritic cell recruitment by chemokines. Transplantation 73, S7–S11.CrossRefPubMedGoogle Scholar
  11. Connor, J. P., Ferrer, K., Kane, J. P. and Goldberg, J. M. (1999) Evaluation of Langerhans’ cells in the cervical epithelium of women with cervical intraepithelial neoplasia. Gynecol. Oncol. 75, 130–135.CrossRefPubMedGoogle Scholar
  12. Cremel, M., Hamzeh-Cognasse, H., Genin, C. and Delezay, O. (2006) Female genital tract immunization: evaluation of candidate immunoadjuvants on epithelial cell secretion of CCL20 and dendritic/Langerhans cell maturation. Vaccine 24, 5744–5754.CrossRefPubMedGoogle Scholar
  13. Cumberbatch, M., Clelland, K., Dearman, R. J. and Kimber, I. (2005) Impact of cutaneous IL-10 on resident epidermal Langerhans’ cells and the development of polarized immune responses. J. Immunol. 175, 43–50.PubMedGoogle Scholar
  14. Del Mistro, A., Insacco, E., Cinel, A., Bonaldi, L., Minucci, D. and Chieco-Bianchi, L. (1994) Human papillomavirus infections of the genital region in human immunodeficiency virus seropositive women: integration of type 16 correlates with rapid progression. Eur. J. Gynaecol. Oncol. 15, 50–58.PubMedGoogle Scholar
  15. Eckert, L. O., Watts, D. H., Koutsky, L. A., Hawes, S. E., Stevens, C. E., Kuypers, J. and Kiviat, N. B. (1999) A matched prospective study of human immunodeficiency virus serostatus, human papillomavirus DNA, and cervical lesions detected by cytology and colposcopy. Infect. Dis. Obstet. Gynecol. 7, 158–164.CrossRefPubMedGoogle Scholar
  16. Fausch, S. C., Fahey, L. M., Da Silva, D. M. and Kast, W. M. (2005) Human papillomavirus can escape immune recognition through Langerhans cell phosphoinositide 3-kinase activation. J. Immunol. 174, 7172–7178.PubMedGoogle Scholar
  17. Ferrara, A., Nonn, M., Sehr, P., Schreckenberger, C., Pawlita, M., Durst, M., Schneider, A. and Kaufmann, A. M. (2003) Dendritic cell-based tumor vaccine for cervical cancer II: results of a clinical pilot study in 15 individual patients. J. Cancer Res. Clin. Oncol. 129, 521–530.CrossRefPubMedGoogle Scholar
  18. Griffiths, C. E., Dearman, R. J., Cumberbatch, M. and Kimber, I. (2005) Cytokines and Langerhans cell mobilisation in mouse and man. Cytokine 32, 67–70.CrossRefPubMedGoogle Scholar
  19. Groves, R. W., Allen, M. H., Ross, E. L., Barker, J. N. and MacDonald, D. M. (1995) Tumour necrosis factor alpha is pro-inflammatory in normal human skin and modulates cutaneous adhesion molecule expression. Br. J. Dermatol. 132, 345–352.CrossRefPubMedGoogle Scholar
  20. Guess, J. C. and McCance, D. J. (2005) 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. 79, 14852–14862.CrossRefPubMedGoogle Scholar
  21. Hawthorn, R. J. and MacLean, A. B. (1987) Langerhans’ cell density in the normal exocervical epithelium and in the cervical intraepithelial neoplasia. Br. J. Obstet. Gynaecol. 94, 815–818.PubMedGoogle Scholar
  22. Hawthorn, R. J., Murdoch, J. B., MacLean, A. B. and MacKie, R. M. (1988) Langerhans’ cells and subtypes of human papillomavirus in cervical intraepithelial neoplasia. BMJ 297, 643–646.CrossRefPubMedGoogle Scholar
  23. Hubert, P., Caberg, J. H., Gilles, C., Bousarghin, L., Franzen-Detrooz, E., Boniver, J. and Delvenne, P. (2005) E-cadherin-dependent adhesion of dendritic and Langerhans cells to keratinocytes is defective in cervical human papillomavirus-associated (pre)neoplastic lesions. J. Pathol. 206, 346–355.CrossRefPubMedGoogle Scholar
  24. Jimenez-Flores, R., Mendez-Cruz, R., Ojeda-Ortiz, J., Munoz-Molina, R., Balderas-Carrillo, O., de la Luz Diaz-Soberanes, M., Lebecque, S., Saeland, S., Daneri-Navarro, A., Garcia-Carranca, A., Ullrich, S. E. and Flores-Romo, L. (2006) High-risk human papilloma virus infection decreases the frequency of dendritic Langerhans’ cells in the human female genital tract. Immunology 117, 220–228.CrossRefPubMedGoogle Scholar
  25. Lee, B. N., Follen, M., Rodriquez, G., Shen, D. Y., Malpica, A., Shearer, W. T. and Reuben, J. M. (2006) Deficiencies in myeloid antigen-presenting cells in women with cervical squamous intraepithelial lesions. Cancer 107, 999–1007.CrossRefPubMedGoogle Scholar
  26. Ling, M., Kanayama, M., Roden, R. and Wu, T. C. (2000) Preventive and therapeutic vaccines for human papillomavirus-associated cervical cancers. J. Biomed. Sci. 7, 341–356.CrossRefPubMedGoogle Scholar
  27. Mahdavi, A. and Monk, B. J. (2005) Vaccines against human papillomavirus and cervical cancer: promises and challenges. Oncologist 10, 528–538.CrossRefPubMedGoogle Scholar
  28. Matthews, K., Leong, C. M., Baxter, L., Inglis, E., Yun, K., Backstrom, B. T., Doorbar, J. and Hibma, M. (2003) Depletion of Langerhans cells in human papillomavirus type 16-infected skin is associated with E6-mediated down regulation of E-cadherin. J. Virol. 77, 8378–8385.CrossRefPubMedGoogle Scholar
  29. Morelli, A. E., Sananes, C., Di Paola, G., Paredes, A. and Fainboim, L. (1993) Relationship between types of human papillomavirus and Langerhans’ cells in cervical condyloma and intraepithelial neoplasia. Am. J. Clin. Pathol. 99, 200–206.PubMedGoogle Scholar
  30. Morris, H. H., Gatter, K. C., Sykes, G., Casemore, V. and Mason, D. Y. (1983) Langerhans’ cells in human cervical epithelium: effects of wart virus infection and intraepithelial neoplasia. Br. J. Obstet. Gynaecol. 90, 412–420.PubMedGoogle Scholar
  31. Park, T. W., Fujiwara, H. and Wright, T. C. (1995) Molecular biology of cervical cancer and its precursors. Cancer 76, 1902–1913.CrossRefPubMedGoogle Scholar
  32. Santin, A. D., Bellone, S., Palmieri, M., Ravaggi, A., Romani, C., Tassi, R., Roman, J. J., Burnett, A., Pecorelli, S. and Cannon, M. J. (2006) HPV16/18 E7-pulsed dendritic cell vaccination in cervical cancer patients with recurrent disease refractory to standard treatment modalities. Gynecol. Oncol. 100, 469–478.CrossRefPubMedGoogle Scholar
  33. Sasagawa, T., Tani, M., Basha, W., Rose, R. C., Tohda, H., Giga-Hama, Y., Azar, K. K., Yasuda, H., Sakai, A. and Inoue, M. (2005) A human papillomavirus type 16 vaccine by oral delivery of L1 protein. Virus Res. 110, 81–90.CrossRefPubMedGoogle Scholar
  34. Scott, M., Nakagawa, M. and Moscicki, A. B. (2001) Cell-mediated immune response to human papillomavirus infection. Clin. Diagn. Lab. Immunol. 8, 209–220.PubMedGoogle Scholar
  35. Tay, S. K., Jenkins, D., Maddox, P., Campion, M. and Singer, A. (1987) Subpopulations of Langerhans’ cells in cervical neoplasia. Br. J. Obstet. Gynaecol. 94, 10–15.PubMedGoogle Scholar
  36. Tindle, R. W. (2002) Immune evasion in human papillomavirus-associated cervical cancer. Nat. Rev. Cancer 2, 59–65.CrossRefPubMedGoogle Scholar
  37. Uchimura, N. S., Ribalta, J. C., Focchi, J., Simoes, M. J., Uchimura, T. T. and Silva, E. S. (2004) Evaluation of Langerhans’ cells in human papillomavirus-associated squamous intraepithelial lesions of the uterine cervix. Clin. Exp. Obstet. Gynecol. 31, 260–262.PubMedGoogle Scholar
  38. Viac, J., Guerin-Reverchon, I., Chardonnet, Y. and Bremond, A. (1990) Langerhans cells and epithelial cell modifications in cervical intraepithelial neoplasia: correlation with human papillomavirus infection. Immunobiology 180, 328–338.PubMedGoogle Scholar
  39. Walboomers, J. M., Jacobs, M. V., Manos, M. M., Bosch, F. X., Kummer, J. A., Shah, K. V., Snijders, P. J., Peto, J., Meijer, C. J. and Munoz, N. (1999) Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J. Pathol. 189, 12–19.CrossRefPubMedGoogle Scholar
  40. Walker, F., Adle-Biassette, H., Madelenat, P., Henin, D. and Lehy, T. (2005) Increased apoptosis in cervical intraepithelial neoplasia associated with HIV infection: implication of oncogenic human papillomavirus, caspases, and Langerhans cells. Clin. Cancer Res. 11, 2451–2458.CrossRefPubMedGoogle Scholar
  41. Wang, B., Amerio, P. and Sauder, D. N. (1999) Role of cytokines in epidermal Langerhans cell migration. J. Leukoc. Biol. 66, 33–39.PubMedGoogle Scholar
  42. Younes, M. S., Robertson, E. M. and Bencosme, S. A. (1968) Electron microscope observations on Langerhans cells in the cervix. Am. J. Obstet. Gynecol. 102, 397–403.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Alagar Manickam
    • 1
  • Muthukumaran Sivanandham
    • 2
  • Irina L. Tourkova
    • 3
  1. 1.Department of BiotechnologyGovernment College of TechnologyIndia
  2. 2.Department of BiotechnologySri Venkateswara College of EngineeringIndia
  3. 3.Department of PathologyUniversity of PittsburghPittsburghUSA

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