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A reversed CD4/CD8 ratio of tumor-infiltrating lymphocytes and a high percentage of CD4+FOXP3+ regulatory T cells are significantly associated with clinical outcome in squamous cell carcinoma of the cervix

Cellular & Molecular Immunology volume 8, pages 59–66 (2011)Cite this article

Abstract

In this study, 40 biopsy samples collected from cervical cancer patients at the First Affiliated Hospital of Xi'an Jiaotong University, China, were retrospectively assessed using immunohistochemistry for CD4+ and CD8+ tumor-infiltrating lymphocytes (TILs) and were analyzed for the expression of FOXP3, OX40, granzyme B (GrB) and perforin (Prf). The proliferating index of the TILs was determined by assessing Ki67 expression. We determined the prognostic value of low and high numbers of TILs on survival by performing Kaplan–Meier analysis using median values as the cut-off points. Except for the number of CD4+FOXP3+ regulatory T cells (Tregs) and the CD4/CD8 ratio, none of the CD4+, CD8+, OX40+, GrB+ or Prf+ TILs were associated with the overall 5-year survival rate. The 5-year survival rate was significantly lower in patients who had a high percentage of Tregs as compared with the those who had a lower percentage (35.3% versus 88.9%, P=0.001), while the 5-year survival rate was significantly higher in patients with a high CD4/CD8 ratio as compared with patients who had a low CD4/CD8 ratio (82.4% versus 44.4%, P=0.029). When we considered the deaths and surviving cases as separate groups, we found that both the number of CD4+ T cells and the CD4/CD8 ratio were significantly lower in patients who died as compared with those who survived (26.33±11.80 versus 47.79±38.18, P=0.023 and 0.60±0.25 versus 1.17±1.02, P=0.019, respectively). In conclusion, decreased proportions of tumor-infiltrating CD4+ T cells with high percentages of Tregs and reversed CD4/CD8 ratios were significantly associated with the clinical outcome of patients with cervical carcinoma.

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References

  1. Umansky V, Schirrmacher V, Rocha M . New insights into tumor-host interactions in lymphoma metastasis. J Mol Med 1996; 74: 353–363.

    Article  CAS  PubMed  Google Scholar 

  2. Disis ML, Bernhard H, Jaffee EM . Use of tumour-responsive T cells as cancer treatment. Lancet 2009; 373: 673–683.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Ruffini E, Asioli S, Filosso PL, Lyberis P, Bruna MC et al. Clinical significance of tumor-infiltrating lymphocytes in lung neoplasms. Ann Thorac Surg 2009; 87: 365–371.

    Article  PubMed  Google Scholar 

  4. Leffers N, Gooden MJ, de Jong RA, Hoogeboom BN, ten Hoor KA, Hollema H et al. Prognostic significance of tumor-infiltrating T-lymphocytes in primary and metastatic lesions of advanced stage ovarian cancer. Cancer Immunol Immunother 2009; 58: 449–459.

    Article  PubMed  Google Scholar 

  5. Tomsova M, Melichar B, Sedlakova I, Steiner I . Prognostic significance of CD3+ tumor infiltrating lymphocytes in ovarian carcinoma. Gynecol Oncol 2008; 108: 415–420.

    Article  CAS  PubMed  Google Scholar 

  6. Dunn GP, Dunn IF, Curry WT . Focus on TILs: prognostic significance of tumor infiltrating lymphocytes in human glioma. Cancer Immun. 2007; 7: 12.

    PubMed  PubMed Central  Google Scholar 

  7. Couzin J . Cancer. T cells a boon for colon cancer prognosis. Science 2006; 313: 1868–1869.

    Article  CAS  PubMed  Google Scholar 

  8. Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F et al. Intraepithelial CD8+ tumor infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci USA 2005; 102: 18538–18543.

    Article  CAS  PubMed  Google Scholar 

  9. Prall F, Duhrkop T, Weirich V, Ostwald C, Lenz P, Nizze H et al. Prognostic role of CD8+ tumor-infiltrating lymphocytes in stage III colorectal cancer with and without microsatellite instability. Hum Pathol 2004; 35: 808–816.

    Article  CAS  PubMed  Google Scholar 

  10. Fukunaga A, Miyamoto M, Cho Y, Murakami S, Kawarada Y, Oshikiri T et al. CD8+ tumor-infiltrating lymphocytes together with CD4+ tumor-infiltrating lymphocytes and dendritic cells improve the prognosis of patients with pancreatic adenocarcinoma. Pancreas 2004; 28: 26–31.

    Article  Google Scholar 

  11. Pardoll DM, Topalian SL . The role of CD4+ T cell responses in antitumor immunity. Curr Opin Immunol 1998; 10: 588–594.

    Article  CAS  PubMed  Google Scholar 

  12. Toes RE, Ossendorp F, Offringa R, Melief CJ . CD4 T cells and their role in antitumor immune responses. J Exp Med 1999; 189: 753–756.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ho WY, Yee C, Greenberg PD . Adoptive therapy with CD8+ T cells: it may get by with a little help from its friends. J Clin Invest 2002; 110: 1415–1417.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bevan MJ . Helping the CD8+ T-cell response. Nat Rev Immunol 2004; 4: 595–602.

    Article  CAS  PubMed  Google Scholar 

  15. Dudley ME, Wunderlich JR, Robbins PF, Yang JC, Hwu P, Schwartzentruber DJ et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 2002; 19: 850–854.

    Article  Google Scholar 

  16. Sobhani I, Le Gouvello S . Critical role for CD8+FoxP3+ regulatory T cells in colon cancer immune response in humans. Gut 2009; 58: 743–744.

    Article  CAS  PubMed  Google Scholar 

  17. Salama P, Phillips M, Grieu F, Morris M, Zeps N, Joseph D et al. Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol 2009; 27: 186–192.

    Article  PubMed  Google Scholar 

  18. Gjerdrum LM, Woetmann A, Odum N, Burton CM, Rossen K, Skovgaard GL et al. FOXP3+ regulatory T cells in cutaneous T-cell lymphomas: association with disease stage and survival. Leukemia 2007; 21: 2512–2518.

    Article  CAS  PubMed  Google Scholar 

  19. Fu J, Xu D, Liu Z, Shi M, Zhao P, Fu B et al. Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology 2007; 132: 2328–2339.

    Article  PubMed  Google Scholar 

  20. Yu P, Fu YX . Tumor-infiltrating T lymphocytes: friends or foes? Lab Invest 2006; 86: 231–245.

    Article  CAS  PubMed  Google Scholar 

  21. Sasaki A, Tanaka F, Mimori K, Inoue H, Kai S, Shibata K et al. Prognostic value of tumor-infiltrating FOXP3+ regulatory T cells in patients with hepatocellular carcinoma. Eur J Surg Oncol 2008; 34: 173–179.

    Article  CAS  PubMed  Google Scholar 

  22. Yoshioka T, Miyamoto M, Cho Y, Ishikawa K, Tsuchikawa T, Kadoya M et al. Infiltrating regulatory T cell numbers is not a factor to predict patient's survival in oesophageal squamous cell carcinoma. Br J Cancer 2008; 98: 1258–1263.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lee NR, Song EK, Jang KY, Choi HN, Moon WS, Kwon K et al. Prognostic impact of tumor infiltrating FOXP3 positive regulatory T cells in diffuse large B-cell lymphoma at diagnosis. Leuk Lymphoma 2008; 49: 247–256.

    Article  CAS  PubMed  Google Scholar 

  24. Grabenbauer GG, Lahmer G, Distel L, Niedobitek G . Tumor-infiltrating cytotoxic T cells but not regulatory T cells predict outcome in anal squamous cell carcinoma. Clin Cancer Res 2006; 12: 3355–3360.

    Article  CAS  PubMed  Google Scholar 

  25. Yan W, Le Z, Hongyan W, Juxiang X, Lusheng S, Yili W . The ex vivo microenvironments in MLTC of poorly immunogenic tumor cells facilitate polarization of CD4+CD25+ regulatory T cells. Cell Mol Immunol 2006; 3: 123–129.

    Google Scholar 

  26. Patel S, Chiplunkar S . Host immune responses to cervical cancer. Curr Opin Obstet Gyneco 2009; 21: 54–59.

    Article  Google Scholar 

  27. Loddenkemper C, Hoffmann C, Stanke J, Nagorsen D, Baron U, Olek S et al. Regulatory (FOXP3+) T cells as target for immune therapy of cervical intraepithelial neoplasia and cervical cancer. Cancer Sci 2009; 100: 1112–1117.

    Article  CAS  PubMed  Google Scholar 

  28. Bosch FX, Manos MM, Munoz N, Sherman M, Jansen AM et al. Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. International biological study on cervical cancer (IBSCC) Study Group. J Natl Cancer Inst 1995; 87: 796–802.

    Article  CAS  PubMed  Google Scholar 

  29. Munoz N, Bosch FX, de Sanjose S, Herrero R, Castellsagué X, Shah KV et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003; 348: 518–527.

    Article  Google Scholar 

  30. Shah W, Hongwei C, Jin Z, Lifang D, Jun Y, Yili W . The prevalence of human papillomavirus type 58 in Chinese patients with cervical carcinoma and its influence on survival. Clin Oncol (R Coll Radiol). 2009; 21: 768–774.

    Article  Google Scholar 

  31. Piersma SJ, Jordanova ES, van Poelgeest MI, Kwappenberg KM, van der Hulst JM, Drijfhout JW et al. High Number of Intraepithelial CD8+ tumor-infiltrating lymphocytes is associated with the absence of lymph node metastases in patients with large early-stage cervical cancer. Cancer Res 2007; 67: 354–361.

    Article  CAS  PubMed  Google Scholar 

  32. Kondratiev S, Sabo E, Yakirevich E, Lavie O, Resnick MB . Resnick. Intratumoral CD8+ T lymphocytes as a prognostic factor of survival in endometrial carcinoma. Clin Cancer Res 2004; 10: 4450–4456.

    Article  PubMed  Google Scholar 

  33. Chiba T, Ohtani H, Mizoi T, Naito Y, Sato E, Nagura H et al. Intraepithelial CD8+ T-cell-count becomes a prognostic factor after a longer follow-up period in human colorectal carcinoma: possible association with suppression of micrometastasis. Br J Cancer 2004; 91: 1711–1717.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Schumacher K, Haensch W, Roefzaad C, Schlag PM . Prognostic significance of activated CD8+ T cell infiltrations within esophageal carcinomas. Cancer Res 2001; 61: 3932–3936.

    CAS  PubMed  Google Scholar 

  35. Sharma P, Shen Y, Wen S, Yamada S, Jungbluth AA, Gnjatic S et al. CD8 tumor-infiltrating lymphocytes are predictive of survival in muscle-invasive urothelial carcinoma. Proc Natl Acad Sci USA 2007; 104: 3967–3972.

    Article  CAS  PubMed  Google Scholar 

  36. Wakabayashi O, Yamazaki K, Oizumi S, Hommura F, Kinoshita I, Ogura S et al. CD4+ T cells in cancer stroma, not CD8+ T cells in cancer cell nests, are associated with favorable prognosis in human non-small cell lung cancers. Cancer Sci 2003; 94: 1003–1009.

    Article  CAS  PubMed  Google Scholar 

  37. Nakano O, Sato M, Naito Y, Suzuki K, Orikasa S, Aizawa M et al. Proliferative activity of intratumoral CD8+ T-lymphocytes as a prognostic factor in human renal cell carcinoma: clinicopathologic demonstration of antitumor immunity. Cancer Res 2001; 61: 5132–5136.

    CAS  PubMed  Google Scholar 

  38. Monnier-Benoit S, Mauny F, Riethmuller D, Guerrini JS, Căpîlna M, Félix S et al. Immunohistochemical analysis of CD4+ and CD8+ T-cell subsets in high risk human papillomavirus-associated pre-malignant and malignant lesions of the uterine cervix. Gynecol Oncol 2006; 102: 22–31.

    Article  PubMed  Google Scholar 

  39. Santin AD, Bellone S, Palmieri M, Bossini B, Roman JJ, Cannon MJ et al. Induction of tumor-specific cytotoxicity in tumor infiltrating lymphocytes by HPV16 and HPV18 E7-pulsed autologous dendritic cells in patients with cancer of the uterine cervix. Gynecol Oncol 2003; 89: 271–280.

    Article  PubMed  Google Scholar 

  40. Baniyash M . TCR ζ-chain down regulation: curtailing an excessive inflammatory immune response. Nat Rev Immunol 2004; 4: 675–687.

    Article  CAS  PubMed  Google Scholar 

  41. Wang HY, He JJ, Shi QF, Lai BC, Ding HY, Zheng J et al. Clinicopathological significance of cytotoxic lymphocytes in breast cancer and draining lymph nodes. Zhonghua Bing Li Xue Za Zhi. 2009; 38: 384–388. Chinese.

    PubMed  Google Scholar 

  42. Nedergaard BS, Ladekarl M, Thomsen HF, Nyengaard JR, Nielsen K . Low density of CD3+, CD4+ and CD8+ cells is associated with increased risk of relapse in squamous cell cervical cancer. Br J Cancer 2007; 97: 1135–1138.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Badoual C, Hans S, Rodriguez J, Peyrard S, Klein C, Agueznay Nel H et al. Prognostic value of tumor-infiltrating CD4+ T-cell subpopulations in head and neck cancers. Clin Cancer Res 2006; 12: 465–472.

    Article  CAS  PubMed  Google Scholar 

  44. Sakaguchi S . Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 2004; 22: 531–562.

    Article  CAS  PubMed  Google Scholar 

  45. Baecher-Allan C, Viglietta V, Hafler DA . Human CD4+CD25+ regulatory T cells. Semin Immunol 2004; 16: 89–98.

    Article  CAS  PubMed  Google Scholar 

  46. Onizuka S, Tawara I, Shimizu J, Sakaguchi S, Fujita T, Nakayama E . Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor) monoclonal antibody. Cancer Res 1999; 59: 3128–3133

    CAS  PubMed  Google Scholar 

  47. Shimizu J, Yamazaki S, Sakaguchi S . Induction of tumor immunityby removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol 1999; 163: 5211–5218.

    CAS  PubMed  Google Scholar 

  48. Nishikawa H, Kato T, Tawara I, Takemitsu T, Saito K, Wang L et al. Accelerated chemically induced tumor development mediated by CD4+CD25+ regulatory T cells in wild-type hosts. Proc Natl Acad Sci USA 2005; 102: 9253–9257.

    Article  CAS  PubMed  Google Scholar 

  49. Sutmuller RP, van Duivenvoorde LM, van Elsas A, Schumacher TN, Wildenberg ME, Allison JP et al. Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25+ regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses. J Exp Med 2001; 194: 823–832.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Tanaka H, Tanaka J, Kjaergaard J, Shu S . Depletion of CD4+CD25+ regulatory cells augments the generation of specific immune T cells in tumor-draining lymph nodes. J Immunother 2002; 25: 207–217.

    Article  CAS  PubMed  Google Scholar 

  51. van der Burg SH, Piersma SJ, de Jong A, van der Hulst JM, Kwappenberg KM, van den Hende M et al. Association of cervical cancer with the presence of CD4+ regulatory T cells specific for human papillomavirus antigens. Proc Natl Acad Sci USA 2007; 104: 12087–12092.

    Article  CAS  PubMed  Google Scholar 

  52. Sheu BC, Hsu SM, Ho HN, Lin RH, Torng PL, Huang SC . Reversed CD4/CD8 ratios of tumor-infiltrating lymphocytes are correlated with the progression of human cervical carcinoma. Cancer 1999; 86: 1537–1543.

    Article  CAS  PubMed  Google Scholar 

  53. Chen L, Linsley PS, Hellström KE . Costimulation of T cells for tumor immunity. Immunol Today 1993; 14: 483–486.

    Article  CAS  PubMed  Google Scholar 

  54. Cheng TY, Wu JT, Lin RH . Induction of tumor-specific T cell response by cognating tumor cells with foreign antigen-primed Th cells. Int Immunol 1998; 10: 1397–1406.

    Article  CAS  PubMed  Google Scholar 

  55. Greenberg PD . Adoptive T cells therapy of tumors: mechanisms operative in the recognition and elimination of tumor cells. Adv Immunol 1991; 49: 281–355.

    Article  CAS  PubMed  Google Scholar 

  56. Baskar S, Glimcher L, Nabavi N, Jones RT, Ostrand-Rosenberg S . Major histocompatibility complex II1B7211 tumor cells are potent vaccines for stimulating tumor rejection on tumor-bearing mice. J Exp Med 1995; 181: 619–629.

    Article  CAS  PubMed  Google Scholar 

  57. Unitt E, Marshall A, Gelson W, Rushbrook SM, Davies S, Vowler S et al. Tumour lymphocytic infiltrate and recurrence of hepatocellular carcinoma following liver transplantation. J Hepatol 2006; 45: 246–253.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank the Department of Radiation Oncology of the First Affiliated Hospital of the Medical College of Xi'an Jiaotong University for providing tissue samples and clinical data. This study was supported by the Higher Education Commission of Pakistan and the Foundation of Bureau of Health (Grant No. 04D13) of Shaanxi Province, China.

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Authors and Affiliations

  1. Center for Cancer Research, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China

    Walayat Shah, Xiaofei Yan, Hongwei Chen & Yili Wang

  2. Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Khyber-Pakhtoonkhwa, Pakistan

    Walayat Shah

  3. Department of Biochemistry, School of Medicine, Xi'an Jiaotong University, Xi'an, China

    Xiaofei Yan

  4. Department of Pathology, Ningxia Medical University, Yinchuan, China

    Li Jing

  5. Department of Pathology, Xi'an Medical College, Xi'an, China

    Yi Zhou

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Correspondence to Hongwei Chen or Yili Wang.

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Shah, W., Yan, X., Jing, L. et al. A reversed CD4/CD8 ratio of tumor-infiltrating lymphocytes and a high percentage of CD4+FOXP3+ regulatory T cells are significantly associated with clinical outcome in squamous cell carcinoma of the cervix. Cell Mol Immunol 8, 59–66 (2011). https://doi.org/10.1038/cmi.2010.56

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