Tumor Biology

, Volume 37, Issue 12, pp 16093–16101 | Cite as

Interleukin 10 promotes immune response by increasing the survival of activated CD8+ T cells in human papillomavirus 16-infected cervical cancer

  • Li Li
  • Yan Ma
  • Shuang Liu
  • Jin Zhang
  • Xin-Yan Xu
Original Article


Human papillomavirus (HPV)-specific CD8+ T cells are present in HPV-infected cervical cancer patients and have demonstrated potent antitumor properties. However, these cells cannot control tumor progression in most patients. To investigate the underlying mechanisms involved in suppressing or promoting CD8+ T cell functions, we focused on interleukin 10 (IL-10), a pleiotropic cytokine with controversial roles in antitumor immunity. We found that compared to healthy controls, circulating CD8+ T cells in HPV 16-infected cervical cancer patients expressed significantly higher levels of IL-10. Interestingly, these CD8+ T cells from cervical cancer patients, but not those from healthy controls, responded to HPV 16 E6/E7 peptide stimulation by increasing IL-10 expression, demonstrating an antigen-specific IL-10 release. Addition of exogenous IL-10 improved the survival, but did not increase the proliferation, of peptide-stimulated CD8+ T cells. CD8+ T cells cultured in the presence of IL-10 also resulted in significantly higher interferon gamma (IFN-gamma) and granzyme B concentration, primarily due to improved cell survival. In resected cervical tumors, the frequency of tumor-infiltrating IL-10+ CD8+ T cells was positively correlated with the frequency of tumor-infiltrating IFN-gamma+ and granzyme B+ CD8+ T cells. Tumor-associated macrophages were more potent than peripheral blood monocyte-derived macrophages at inducing IL-10 expression in CD8+ T cells, possibly explaining the elevated IL-10+ CD8+ T cell frequency in cervical cancer patients. Together, these results are consistent with an immunostimulatory role of IL-10, which promoted CD8+ T cell response by increasing the survival of activated CD8+ T cells.


CD8+ T cells HPV Cervical cancer 



We thank DICAT Biomedical Computation Centre for data analysis.

Compliance with ethical standards

Conflicts of interest



  1. 1.
    Woodman C, Collins S, Young C, Young LS. The natural history of cervical HPV infection: unresolved issues—ProQuest. Nat Rev Cancer. (2007):11–22.Google Scholar
  2. 2.
    Frazer IH. Prevention of cervical cancer through papillomavirus vaccination. Nat. Rev. Immunol. 2004;4:46–54.CrossRefPubMedGoogle Scholar
  3. 3.
    Tindle RW. Immune evasion in human papillomavirus-associated cervical cancer. Nat Rev Cancer. 2002;2:1–7.CrossRefGoogle Scholar
  4. 4.
    Evans C, Bauer S, Grubert T, Brucker C, Baur S, Heeg K, et al. HLA-A2-restricted peripheral blood cytolytic T lymphocyte response to HPV type 16 proteins E6 and E7 from patients with neoplastic cervical lesions. Cancer Immunol Immunother. 1996;42:151–60.CrossRefPubMedGoogle Scholar
  5. 5.
    Youde SJ, Dunbar PRR, Evans EML, Fiander AN, Borysiewicz LK, Cerundolo V, et al. Use of fluorogenic histocompatibility leukocyte antigen-a*0201/HPV 16 E7 peptide complexes to isolate rare human cytotoxic T-lymphocyte-recognizing endogenous human papillomavirus antigens. Cancer Res. 2000;60:365–71.PubMedGoogle Scholar
  6. 6.
    Liu D-W, Yang Y-C, Lin H-F, Lin M-F, Cheng Y-W, Chu C-C, et al. Cytotoxic T-lymphocyte responses to human papillomavirus type 16 E5 and E7 proteins and HLA-A*0201-restricted T-cell peptides in cervical cancer patients. J Virol. 2007;81:2869–79.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Ressing ME, Van Driel WJ, Cells E, Sette A, Brandt RMP, Hartman M, et al. Occasional memory cytotoxic T-cell responses of patients with human papillomavirus type 16-positive cervical lesions against a human leukocyte antigen-a * 0201-restricted E7-encoded epitope. Cancer Res. 1996;56:582–8.PubMedGoogle Scholar
  8. 8.
    Rudolf MP, Man S, Melief CJM, Sette A, Kast WM, Human T. Cell responses to HLA-A-restricted high binding affinity peptides of human papillomavirus type 18 proteins E6 and E7. Clin Cancer Res. 2001;7:788–95.Google Scholar
  9. 9.
    Stevanović S, Draper LM, Langhan MM, Campbell TE, Kwong ML, Wunderlich JR, et al. Complete regression of metastatic cervical cancer after treatment with human papillomavirus-targeted tumor-infiltrating T cells. J Clin Oncol. 2015;33:1543–50.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Ouyang W, Rutz S, Crellin NK, Valdez PA, Hymowitz SG. Regulation and functions of the IL-10 family of cytokines in inflammation and disease. Annu Rev Immunol. 2011;29:71–7109.CrossRefPubMedGoogle Scholar
  11. 11.
    Saraiva M, O’Garra A. The regulation of IL-10 production by immune cells. Nat. Rev. Immunol. 2010;10:170–81.CrossRefPubMedGoogle Scholar
  12. 12.
    Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol. 2001;19:683–765.CrossRefPubMedGoogle Scholar
  13. 13.
    Beckebaum S, Zhang X, Chen X, Yu Z, Frilling A, Dworacki G, et al. Increased levels of interleukin-10 in serum from patients with hepatocellular carcinoma correlate with profound numerical deficiencies and immature phenotype of circulating dendritic cell subsets. Clin Cancer Res. 2004;10:7260–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Sarris AH, Kliche K-O, Pethambaram P, Preti A, Tucker S, Jackow C, et al. Interleukin-10 levels are often elevated in serum of adults with Hodgkin’s disease and are associated with inferior failure-free survival. Ann Onc. 1999;10:433–40.CrossRefGoogle Scholar
  15. 15.
    Sredni B, Weil M, Khomenok G, Lebenthal I, Teitz S, Mardor Y, et al. Ammonium trichloro(dioxoethylene-o,o’)tellurate (AS101) sensitizes tumors to chemotherapy by inhibiting the tumor interleukin 10 autocrine loop. Cancer Res. 2004;64:1843–52.CrossRefPubMedGoogle Scholar
  16. 16.
    Alas S, Emmanouilides C, Bonavida B. Inhibition of interleukin 10 by rituximab results in down-regulation of Bcl-2 and sensitization of B-cell non-Hodgkin’s lymphoma to apoptosis. Clin Cancer Res. 2001;7:709–23.PubMedGoogle Scholar
  17. 17.
    Mumm JB, Emmerich J, Zhang X, Chan I, Wu L, Mauze S, et al. IL-10 elicits IFNγ-dependent tumor immune surveillance. Cancer Cell. 2011;20:781–96.CrossRefPubMedGoogle Scholar
  18. 18.
    Emmerich J, Mumm JB, Chan IH, LaFace D, Truong H, McClanahan T, et al. IL-10 directly activates and expands tumor-resident CD8+ T cells without de novo infiltration from secondary lymphoid organs. Cancer Res. 2012;72:3570–81.CrossRefPubMedGoogle Scholar
  19. 19.
    Fujii S -i. Interleukin-10 promotes the maintenance of antitumor CD8+ T-cell effector function in situ. Blood [internet]. American Society of Hematology. 2001;98:2143–51.Google Scholar
  20. 20.
    Huang S, Xie K, Bucana CD, Ullrich SE, Bar-Eli M. Interleukin 10 suppresses tumor growth and metastasis of human melanoma cells: potential inhibition of angiogenesis. Clin Cancer Res. 1996;2:1969–79.PubMedGoogle Scholar
  21. 21.
    Stearns ME, Garcia FU, Fudge K, Rhim J, Wang M. Role of interleukin 10 and transforming growth factor beta1 in the angiogenesis and metastasis of human prostate primary tumor lines from orthotopic implants in severe combined immunodeficiency mice. Clin Cancer Res. 1999;5:711–20.PubMedGoogle Scholar
  22. 22.
    Faupel-Badger JM, Kidd LCR, Albanes D, Virtamo J, Woodson K, Tangrea JA. Association of IL-10 polymorphisms with prostate cancer risk and grade of disease. Cancer Causes Control. 2008;19:119–24.CrossRefPubMedGoogle Scholar
  23. 23.
    Fujinaga Y, Shimada M, Okazawa K, Fukushima M, Kato I, Fujinaga K. Simultaneous detection and typing of genital human papillomavirus DNA using the polymerase chain reaction. J Gen Virol. 1991;72(Pt 5):1039–44.CrossRefPubMedGoogle Scholar
  24. 24.
    Noble A, Giorgini A, Leggat JA. Cytokine-induced IL-10-secreting CD8 T cells represent a phenotypically distinct suppressor T-cell lineage. Blood. 2006;107:4475–83.CrossRefPubMedGoogle Scholar
  25. 25.
    Trandem K, Zhao J, Fleming E, Perlman S. Highly activated cytotoxic CD8 T cells express protective IL-10 at the peak of coronavirus-induced encephalitis. J Immunol. 2011;186:3642–52.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Vermes I, Haanen C, Steffens-Nakken H, Reutelingsperger CA. Novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled annexin V. J Immunol Methods. 1995;184:39–51.CrossRefPubMedGoogle Scholar
  27. 27.
    Noy R, Pollard JW. Tumor-associated macrophages: from mechanisms to therapy. Immunity. 2014;41:49–61.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Petrillo M, Zannoni GF, Martinelli E, Pedone Anchora L, Ferrandina G, Tropeano G, et al. Polarisation of tumor-associated macrophages toward M2 phenotype correlates with poor response to Chemoradiation and reduced survival in patients with locally advanced cervical cancer. PLoS One. 2015;10:e0136654.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Gajewski TF, Schreiber H, Fu Y-X. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol. 2013;14:1014–22.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Han Q, Shi H, Liu F. CD163(+) M2-type tumor-associated macrophage support the suppression of tumor-infiltrating T cells in osteosarcoma. Int Immunopharmacol. 2016;34:101–6.CrossRefPubMedGoogle Scholar
  31. 31.
    Engelhardt JJ, Boldajipour B, Beemiller P, Pandurangi P, Sorensen C, Werb Z, et al. Marginating dendritic cells of the tumor microenvironment cross-present tumor antigens and stably engage tumor-specific T cells. Cancer Cell. 2012;21:402–17.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Mauri C, Bosma A. Immune regulatory function of B cells. Annu Rev Immunol. 2012;30:221–41.CrossRefPubMedGoogle Scholar
  33. 33.
    Restifo NP, Dudley ME, Rosenberg SA. Adoptive immunotherapy for cancer: harnessing the T cell response. Nat Rev Immunol. 2012;12:269–81.CrossRefPubMedGoogle Scholar
  34. 34.
    Rabinovich GA, Gabrilovich D, Sotomayor EM. Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol. 2007;25:267–96.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Murray PJ. The primary mechanism of the IL-10-regulated antiinflammatory response is to selectively inhibit transcription. Proc Natl Acad Sci U S A. 2005;102:8686–91.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Santin AD, Hermonat PL, Ravaggi A, Bellone S, Pecorelli S, Roman JJ, et al. Interleukin-10 increases Th1 cytokine production and cytotoxic potential in human papillomavirus-specific CD8+ cytotoxic T lymphocytes. J Virol. 2000;74:4729–37.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Zhang S, Zhang H, Zhao J. The role of CD4 T cell help for CD8 CTL activation. Biochem Biophys Res Commun. 2009;384:405–8.CrossRefPubMedGoogle Scholar
  38. 38.
    Castellino F, Germain RN. Cooperation between CD4+ and CD8+ T cells: when, where, and how. Annu Rev Immunol. 2006;24:519–40.CrossRefPubMedGoogle Scholar
  39. 39.
    Nakanishi Y, Lu B, Gerard C, Iwasaki A. CD8(+) T lymphocyte mobilization to virus-infected tissue requires CD4(+) T-cell help. Nature. 2009;462:510–3.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Sato T, Terai M, Tamura Y, Alexeev V, Mastrangelo MJ, Selvan SR. Interleukin 10 in the tumor microenvironment: a target for anticancer immunotherapy. Immunol Res. 2011;51:170–82.CrossRefPubMedGoogle Scholar
  41. 41.
    Oft MIL. 10: master switch from tumor-promoting inflammation to antitumor immunity. Cancer. Immunol Res. 2014;2:194–9.Google Scholar
  42. 42.
    Jessup JM, Samara R, Battle P, Laguinge LM. Carcinoembryonic antigen promotes tumor cell survival in liver through an IL-10-dependent pathway. Clin Exp Metastasis. 2004;21:709–17.CrossRefPubMedGoogle Scholar
  43. 43.
    Forssell J, Oberg A, Henriksson ML, Stenling R, Jung A, Palmqvist R. High macrophage infiltration along the tumor front correlates with improved survival in colon cancer. Clin Cancer Res. 2007;13:1472–9.CrossRefPubMedGoogle Scholar
  44. 44.
    Shimura S, Yang G, Ebara S, Wheeler TM, Frolov A, Thompson TC. Reduced infiltration of tumor-associated macrophages in human prostate cancer: association with cancer progression. Cancer Res. 2000;60:5857–61.PubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Li Li
    • 1
  • Yan Ma
    • 1
  • Shuang Liu
    • 1
  • Jin Zhang
    • 1
  • Xin-Yan Xu
    • 1
  1. 1.Department of Gynecology, Third Affiliated HospitalXinjiang Medical UniversityUrumqiChina

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