Journal of Cancer Research and Clinical Oncology

, Volume 139, Issue 11, pp 1845–1852 | Cite as

The appearance of Tregs in cancer nest is a promising independent risk factor in colon cancer

Original Paper

Abstract

Purpose

To investigate the prognostic value of tumor-infiltrating regulatory T cells (Tregs) in the distribution of cancer nest, cancer stroma and normal mucosa and FOXP3-positive cancer cells in colon cancer patients after resection.

Methods

Paraffin blocks of operation resection of primary adenocarcinoma of colon were obtained from ninety patients. The distribution of tumor-infiltrating Tregs was detected by tissue microarray and immunohistochemistry staining technique to evaluate the prognostic effects by Kaplan–Meier and Cox regression analysis using median values as cutoff.

Results

The intratumoral Tregs counts were significantly higher than that in corresponding normal mucosa tissues (P < 0.001); the Tregs counts in cancer nest were significantly lower than that in corresponding cancer stroma tissues (P < 0.001); the increased intratumoral Tregs counts were associated with favorable prognosis (P < 0.05); the presence of Tregs in cancer nest was associated with unfavorable prognosis and was an independent prognostic factor for overall survival (P < 0.05). The appearance of FOXP3-positive cancer cells was associated with worse prognosis (P < 0.05). In addition, the frequency of the presence of FOXP3-positive cancer cells was higher in patients with lymphatic invasion (P < 0.001) and lower in patients with early TNM stage (P < 0.01).

Conclusions

The higher tumor-infiltrating Tregs counts are closely associated with the improved prognostic effects of colon carcinoma. Tregs play different roles in cancer nest and cancer stroma. And the appearance of Tregs in cancer nest is a promising independent risk factor for overall survival in colon carcinoma. FOXP3-positive cancer cells may also be a risk factor for overall survival in colon carcinoma.

Keywords

Colon carcinoma Tregs FOXP3 Prognostic Tissue microarray 

References

  1. Bates GJ, Fox SB, Han C, Leek RD, Garcia JF, Harris AL, Banham AH (2006) Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol 24:5373–5380PubMedCrossRefGoogle Scholar
  2. Bromberg J, Wang TC (2009) Inflammation and cancer: IL-6 and STAT3 complete the link. Cancer Cell 15:79–80PubMedCrossRefGoogle Scholar
  3. Clarke SL, Betts GJ, Plant A, Wright KL, El-Shanawany TM, Harrop R, Torkington J, Rees BI, Williams GT, Gallimore AM, Godkin AJ (2006) CD4+ CD25+ FOXP3+ regulatory T cells suppress anti-tumor immune responses in patients with colorectal cancer. PLoS One 1:e129PubMedCrossRefGoogle Scholar
  4. Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, Zhu Y, Wei S, Kryczek I, Daniel B, Gordon A, Myers L, Lackner A, Disis ML, Knutson KL, Chen L, Zou W (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10:942–949PubMedCrossRefGoogle Scholar
  5. Frey DM, Droeser RA, Viehl CT, Zlobec I, Lugli A, Zingg U, Oertli D, Kettelhack C, Terracciano L, Tornillo L (2010) High frequency of tumor-infiltrating FOXP3(+) regulatory T cells predicts improved survival in mismatch repair-proficient colorectal cancer patients. Int J Cancer 126:2635–2643PubMedGoogle Scholar
  6. Galon J, Fridman WH, Pages F (2007) The adaptive immunologic microenvironment in colorectal cancer: a novel perspective. Cancer Res 67:1883–1886PubMedCrossRefGoogle Scholar
  7. Gao Q, Qiu SJ, Fan J, Zhou J, Wang XY, Xiao YS, Xu Y, Li YW, Tang ZY (2007) Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol 25:2586–2593PubMedCrossRefGoogle Scholar
  8. Hinz S, Pagerols-Raluy L, Oberg HH, Ammerpohl O, Grussel S, Sipos B, Grutzmann R, Pilarsky C, Ungefroren H, Saeger HD, Kloppel G, Kabelitz D, Kalthoff H (2007) Foxp3 expression in pancreatic carcinoma cells as a novel mechanism of immune evasion in cancer. Cancer Res 67:8344–8350PubMedCrossRefGoogle Scholar
  9. Hiraoka N, Onozato K, Kosuge T, Hirohashi S (2006) Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin Cancer Res 12:5423–5434PubMedCrossRefGoogle Scholar
  10. Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299:1057–1061PubMedCrossRefGoogle Scholar
  11. Jordanova ES, Gorter A, Ayachi O, Prins F, Durrant LG, Kenter GG, van der Burg SH, Fleuren GJ (2008) Human leukocyte antigen class I, MHC class I chain-related molecule A, and CD8+/regulatory T-cell ratio: which variable determines survival of cervical cancer patients? Clin Cancer Res 14:2028–2035PubMedCrossRefGoogle Scholar
  12. Kim M, Grimmig T, Grimm M, Lazariotou M, Meier E, Rosenwald A, Tsaur I, Blaheta R, Heemann U, Germer CT, Waaga-Gasser AM, Gasser M (2013) Expression of foxp3 in colorectal cancer but not in treg cells correlates with disease progression in patients with colorectal cancer. PLoS One 8:e53630PubMedCrossRefGoogle Scholar
  13. Ladoire S, Arnould L, Mignot G, Coudert B, Rebe C, Chalmin F, Vincent J, Bruchard M, Chauffert B, Martin F, Fumoleau P, Ghiringhelli F (2011a) Presence of Foxp3 expression in tumor cells predicts better survival in HER2-overexpressing breast cancer patients treated with neoadjuvant chemotherapy. Breast Cancer Res Treat 125:65–72PubMedCrossRefGoogle Scholar
  14. Ladoire S, Martin F, Ghiringhelli F (2011b) Prognostic role of FOXP3+ regulatory T cells infiltrating human carcinomas: the paradox of colorectal cancer. Cancer Immunol Immunother 60:909–918PubMedCrossRefGoogle Scholar
  15. Li JF, Chu YW, Wang GM, Zhu TY, Rong RM, Hou J, Xu M (2009) The prognostic value of peritumoral regulatory T cells and its correlation with intratumoral cyclooxygenase-2 expression in clear cell renal cell carcinoma. BJU Int 103:399–405PubMedCrossRefGoogle Scholar
  16. Mitry E, Rachet B, Quinn MJ, Cooper N, Coleman MP (2008) Survival from cancer of the rectum in England and Wales up to 2001. Br J Cancer 99(1):S30–S32PubMedCrossRefGoogle Scholar
  17. Numasaki M, Fukushi J, Ono M, Narula SK, Zavodny PJ, Kudo T, Robbins PD, Tahara H, Lotze MT (2003) Interleukin-17 promotes angiogenesis and tumor growth. Blood 101:2620–2627PubMedCrossRefGoogle Scholar
  18. Pages F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R, Mlecnik B, Kirilovsky A, Nilsson M, Damotte D, Meatchi T, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Galon J (2005) Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 353:2654–2666PubMedCrossRefGoogle Scholar
  19. Perrone G, Ruffini PA, Catalano V, Spino C, Santini D, Muretto P, Spoto C, Zingaretti C, Sisti V, Alessandroni P, Giordani P, Cicetti A, D’Emidio S, Morini S, Ruzzo A, Magnani M, Tonini G, Rabitti C, Graziano F (2008) Intratumoural FOXP3-positive regulatory T cells are associated with adverse prognosis in radically resected gastric cancer. Eur J Cancer 44:1875–1882PubMedCrossRefGoogle Scholar
  20. Petersen RP, Campa MJ, Sperlazza J, Conlon D, Joshi MB, Harpole DJ, Patz EJ (2006) Tumor infiltrating Foxp3+ regulatory T-cells are associated with recurrence in pathologic stage I NSCLC patients. Cancer 107:2866–2872PubMedCrossRefGoogle Scholar
  21. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M (1995) Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155:1151–1164PubMedGoogle Scholar
  22. Sakaguchi S, Miyara M, Costantino CM, Hafler DA (2010) FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol 10:490–500PubMedCrossRefGoogle Scholar
  23. Salama P, Phillips M, Grieu F, Morris M, Zeps N, Joseph D, Platell C, Iacopetta B (2009) Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol 27:186–192PubMedCrossRefGoogle Scholar
  24. Tao H, Mimura Y, Aoe K, Kobayashi S, Yamamoto H, Matsuda E, Okabe K, Matsumoto T, Sugi K, Ueoka H (2012) Prognostic potential of FOXP3 expression in non-small cell lung cancer cells combined with tumor-infiltrating regulatory T cells. Lung Cancer 75:95–101PubMedCrossRefGoogle Scholar
  25. Wang L, Liu R, Li W, Chen C, Katoh H, Chen GY, McNally B, Lin L, Zhou P, Zuo T, Cooney KA, Liu Y, Zheng P (2009) Somatic single hits inactivate the X-linked tumor suppressor FOXP3 in the prostate. Cancer Cell 16:336–346PubMedCrossRefGoogle Scholar
  26. Yoon HH, Orrock JM, Foster NR, Sargent DJ, Smyrk TC, Sinicrope FA (2012) Prognostic impact of FoxP3+ regulatory T cells in relation to CD8+ T lymphocyte density in human colon carcinomas. PLoS One 7(8):e42274PubMedCrossRefGoogle Scholar
  27. Zuo T, Wang L, Morrison C, Chang X, Zhang H, Li W, Liu Y, Wang Y, Liu X, Chan MW, Liu JQ, Love R, Liu CG, Godfrey V, Shen R, Huang TH, Yang T, Park BK, Wang CY, Zheng P, Liu Y (2007) FOXP3 is an X-linked breast cancer suppressor gene and an important repressor of the HER-2/ErbB2 oncogene. Cell 129:1275–1286PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Wei Xu
    • 1
  • Hao Liu
    • 1
  • Jun Song
    • 1
  • Hai-Xiao Fu
    • 1
  • Lei Qiu
    • 1
  • Bao-Fu Zhang
    • 2
  • Hui-Zhong Li
    • 2
  • Jin Bai
    • 2
  • Jun-Nian Zheng
    • 2
  1. 1.Department of SurgeryThe Affiliated Hospital of Xuzhou Medical CollegeXuzhouChina
  2. 2.Jiangsu Key Laboratory of Biological Cancer TherapyXuzhou Medical CollegeXuzhouChina

Personalised recommendations