Skip to main content
SpringerLink
Log in

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

  • Original Paper
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • 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 24:5373–5380

    Article  PubMed  Google Scholar 

  • Bromberg J, Wang TC (2009) Inflammation and cancer: IL-6 and STAT3 complete the link. Cancer Cell 15:79–80

    Article  PubMed  CAS  Google Scholar 

  • 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:e129

    Article  PubMed  Google Scholar 

  • 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 10:942–949

    Article  PubMed  CAS  Google Scholar 

  • 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 126:2635–2643

    PubMed  CAS  Google Scholar 

  • Galon J, Fridman WH, Pages F (2007) The adaptive immunologic microenvironment in colorectal cancer: a novel perspective. Cancer Res 67:1883–1886

    Article  PubMed  CAS  Google Scholar 

  • 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 25:2586–2593

    Article  PubMed  Google Scholar 

  • 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 67:8344–8350

    Article  PubMed  CAS  Google Scholar 

  • 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 12:5423–5434

    Article  PubMed  CAS  Google Scholar 

  • Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299:1057–1061

    Article  PubMed  CAS  Google Scholar 

  • 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 14:2028–2035

    Article  PubMed  CAS  Google Scholar 

  • 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:e53630

    Article  PubMed  CAS  Google Scholar 

  • 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 125:65–72

    Article  PubMed  CAS  Google Scholar 

  • 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 60:909–918

    Article  PubMed  CAS  Google Scholar 

  • 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 103:399–405

    Article  PubMed  Google Scholar 

  • 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–S32

    Article  PubMed  Google Scholar 

  • 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 101:2620–2627

    Article  PubMed  CAS  Google Scholar 

  • 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 353:2654–2666

    Article  PubMed  CAS  Google Scholar 

  • 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 44:1875–1882

    Article  PubMed  CAS  Google Scholar 

  • 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 107:2866–2872

    Article  PubMed  Google Scholar 

  • 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 155:1151–1164

    PubMed  CAS  Google Scholar 

  • Sakaguchi S, Miyara M, Costantino CM, Hafler DA (2010) FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol 10:490–500

    Article  PubMed  CAS  Google Scholar 

  • 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 27:186–192

    Article  PubMed  Google Scholar 

  • 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 75:95–101

    Article  PubMed  Google Scholar 

  • 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 16:336–346

    Article  PubMed  CAS  Google Scholar 

  • 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):e42274

    Article  PubMed  CAS  Google Scholar 

  • 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 129:1275–1286

    Article  PubMed  CAS  Google Scholar 

Download references

Conflict of interest

We declare that we have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Surgery, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, 221002, China

    Wei Xu, Hao Liu, Jun Song, Hai-Xiao Fu & Lei Qiu

  2. Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical College, 84 West Huaihai Road, Xuzhou, 221002, Jiangsu, China

    Bao-Fu Zhang, Hui-Zhong Li, Jin Bai & Jun-Nian Zheng

Authors
  1. Wei Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hao Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jun Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hai-Xiao Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lei Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bao-Fu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hui-Zhong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jin Bai
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jun-Nian Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jin Bai or Jun-Nian Zheng.

Additional information

Wei Xu and Hao Liu have contributed equally to this paper.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Xu, W., Liu, H., Song, J. et al. The appearance of Tregs in cancer nest is a promising independent risk factor in colon cancer. J Cancer Res Clin Oncol 139, 1845–1852 (2013). https://doi.org/10.1007/s00432-013-1500-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-013-1500-7

Keywords

Search

Navigation