Advertisement

Cancer Immunology, Immunotherapy

, Volume 59, Issue 5, pp 653–661 | Cite as

Intratumoral CD8+ T/FOXP3+ cell ratio is a predictive marker for survival in patients with colorectal cancer

  • Hiroyuki Suzuki
  • Nobuhito Chikazawa
  • Takehiko Tasaka
  • Junji Wada
  • Akio Yamasaki
  • Yoshiki Kitaura
  • Masae Sozaki
  • Masao Tanaka
  • Hideya Onishi
  • Takashi Morisaki
  • Mitsuo KatanoEmail author
Original Article

Abstract

The human immune system consists of a balance between immune surveillance against non-self antigens and tolerance of self-antigens. CD8+ T cells and CD4+ regulatory T cells (Tregs) are the main players for immune surveillance and tolerance, respectively. We examined immunohistochemically the immunological balance at the tumor site using 94 surgically resected colorectal cancer tissues. Forkhead box P3 (FOXP3)+ cells were considered to be Tregs in the present study. The number of intratumoral FOXP3+ cells (itFOXP3+ cells) was positively correlated with lymph node metastases (P = 0.030). itCD8+ T/itFOXP3+ cell ratio negatively correlated with pathological stages (P = 0.048). Next, relationship between the number of itCD8+ T cells or itFOXP3+ cells and survival prognosis in 94 patients who underwent a curative resection was analyzed. Only itCD8+ T/itFOXP3+ cell ratio positively correlated with disease-free survival (0.023) and overall survival (P = 0.010). Multivariate analysis indicated that itCD8+ T/itFOXP3+ cell ratio is an independent prognostic factor (P = 0.035) of overall survival. The number of itFOXP3+ cells positively correlated with transforming growth factor-beta TGF-β production at the tumor site (P = 0.020). In conclusion, itCD8+ T/itFOXP3+ cell ratio is a predictive marker for both disease-free survival time and overall survival time in patients with colorectal cancer. Importantly, itCD8+ T/itFOXP3+ cell ratio may be an independent prognostic factor. And, tumor-producing TGF-β may contribute to the increased number of itFOXP3+ cells.

Keywords

Colorectal cancer Intratumoral CD8+ T cells Intratumoral FOXP3+ regulatory T cells CD8+ T cell/FOXP3+ cell ratio Prognostic factor 

Abbreviations

Tregs

CD4+ regulatory T cells

FOXP3

Forkhead box P3

itCD8+ T cells

Intratumoral CD8-positive T cells

itFOXP3+ cells

Intratumoral FOXP3-positive cells

itCD8+ T/itFOXP3+ cell ratio

Ratio of number of intratumoral CD8-positive T cells to number of intratumoral FOXP3-positive cells

TILs

Tumor-infiltrating lymphocytes

PBMCs

Peripheral blood mononuclear cells

TGF-β

Transforming growth factor-beta

Notes

Acknowledgments

This study was supported by a General Scientific Research Grant (18591440) from Ministry of Education, Culture, Sports, Science and Technology of Japan. We thank Kaori Nomiyama for skillful technical assistance.

References

  1. 1.
    Akbar AN, Vukmanovic-Stejic M, Taams LS et al (2007) The dynamic co-evolution of memory and regulatory CD4+ T cells in the periphery. Nat Rev Immunol 7:231–237CrossRefPubMedGoogle Scholar
  2. 2.
    Bates GJ, Fox SB, Han C et al (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 24:5373–5380CrossRefPubMedGoogle Scholar
  3. 3.
    Berendt MJ, North RJ (1980) T-cell-mediated suppression of anti-tumor immunity An explanation for progressive growth of an immunogenic tumor. J Exp Med 151:69–80CrossRefPubMedGoogle Scholar
  4. 4.
    Boon T, Cerottini JC, Van den Eynde B et al (1994) Tumor antigens recognized by T lymphocytes. Annu Rev Immunol 12:337–365CrossRefPubMedGoogle Scholar
  5. 5.
    Chen W, Jin W, Hardegen N et al (2003) Conversion of peripheral CD4+ CD25− naive T cells to CD4+ CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 198:1875–1886CrossRefPubMedGoogle Scholar
  6. 6.
    Cohen AM, Tremiterra S, Candela F et al (1991) Prognosis of node-positive colon cancer. Cancer 67:1859–1861CrossRefPubMedGoogle Scholar
  7. 7.
    Curiel TJ, Coukos G, Zou L et al (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10:942–949CrossRefPubMedGoogle Scholar
  8. 8.
    Drake CG, Jaffee E, Pardoll DM (2006) Mechanisms of immune evasion by tumors. Adv Immunol 90:51–81CrossRefPubMedGoogle Scholar
  9. 9.
    Dunn GP, Bruce AT, Ikeda H et al (2002) Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 3:991–998CrossRefPubMedGoogle Scholar
  10. 10.
    Fantini MC, Becker C, Monteleone G et al (2004) Cutting edge: TGF-beta induces a regulatory phenotype in CD4+CD25− T cells through Foxp3 induction and down-regulation of Smad7. J Immunol 172:5149–5153PubMedGoogle Scholar
  11. 11.
    Fu J, Xu D, Liu Z et al (2007) Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology 132:2328–2339CrossRefPubMedGoogle Scholar
  12. 12.
    Galon J, Costes A, Sanchez-Cabo F et al (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313:1960–1964Google Scholar
  13. 13.
    Gao Q, Qiu SJ, Fan J et al (2007) Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol 25:2586–2593CrossRefPubMedGoogle Scholar
  14. 14.
    Grabenbauer GG, Lahmer G, Distel L et al (2006) Tumor-infiltrating cytotoxic T cells but not regulatory T cells predict outcome in anal squamous cell carcinoma. Clin Cancer Res 12:3355–3360CrossRefPubMedGoogle Scholar
  15. 15.
    Hashimoto K, Nio Y, Sumi S et al (2001) Correlation between TGF-b1 and p21 (WAF1/CIP1) expression of matrix metalloproteinases (MMPs) and tissue inhibitors of the matrix metalloproteinases (TIMPs) in human pancreatic carcinoma. Pancreas 22:341–347CrossRefPubMedGoogle Scholar
  16. 16.
    Hiraoka N, Onozato K, Kosuge T et al (2006) Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin Cancer Res 12:5423–5434CrossRefPubMedGoogle Scholar
  17. 17.
    Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299:1057–1061CrossRefPubMedGoogle Scholar
  18. 18.
    Jass JR (1986) Lymphocytic infiltration and survival in rectal cancer. J Clin Pathol 39:585–589CrossRefPubMedGoogle Scholar
  19. 19.
    Ling KL, Pratap SE, Bates GJ et al (2007) Increased frequency of regulatory T cells in peripheral blood and tumour infiltrating lymphocytes in colorectal cancer patients. Cancer Immun 7:7PubMedGoogle Scholar
  20. 20.
    Liyanage UK, Moore TT, Joo HG et al (2002) Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol 169:2756–2761PubMedGoogle Scholar
  21. 21.
    Loddenkemper C, Schernus M, Noutsias M et al (2006) In situ analysis of FOXP3+ regulatory T cells in human colorectal cancer. J Transl Med 4:52CrossRefPubMedGoogle Scholar
  22. 22.
    Maloy KJ, Powrie F (2001) Regulatory T cells in the control of immune pathology. Nat Immunol 2:816–822CrossRefPubMedGoogle Scholar
  23. 23.
    Marie JC, Letterio JJ, Gavin M et al (2005) TGF-beta1 maintains suppressor function and Foxp3 expression in CD4+ CD25+ regulatory T cells. J Exp Med 201:1061–1067CrossRefPubMedGoogle Scholar
  24. 24.
    Naito Y, Saito K, Shiiba K et al (1998) CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res 58:3491–3494PubMedGoogle Scholar
  25. 25.
    Nomura T, Sakaguchi S (2005) Naturally arising CD25+ CD4+ regulatory T cells in tumor immunity. Curr Top Microbiol Immunol 293:287–302CrossRefPubMedGoogle Scholar
  26. 26.
    Peng Y, Laouar Y, Li MO et al (2004) TGF-beta regulates in vivo expansion of Foxp3-expressing CD4+ CD25+ regulatory T cells responsible for protection against diabetes. P Natl Acad Sci USA 101:4572–4577CrossRefGoogle Scholar
  27. 27.
    Ropponen KM, Eskelinen MJ, Lipponen PK et al (1997) Prognostic value of tumour-infiltrating lymphocytes (TILs) in colorectal cancer. J Pathol 182:318–324CrossRefPubMedGoogle Scholar
  28. 28.
    Sakaguchi S, Sakaguchi N, Asano M et al (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
  29. 29.
    Sakaguchi S (2000) Regulatory T cells: key controllers of immunologic self-tolerance. Cell 101:455–458CrossRefPubMedGoogle Scholar
  30. 30.
    Sasada T, Kimura M, Yoshida Y et al (2003) CD4+ CD25+ regulatory T cells in patients with gastrointestinal malignancies: possible involvement of regulatory T cells in disease progression. Cancer 98:1089–1099CrossRefPubMedGoogle Scholar
  31. 31.
    Sato E, Olson SH, Ahn J et al (2005) Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. P Natl Acad Sci USA 102:18538–18543CrossRefGoogle Scholar
  32. 32.
    Shevach EM (2002) CD4+ CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol 2:389–400PubMedGoogle Scholar
  33. 33.
    Sundrud MS, Rao A (2007) New twists of T cell fate: control of T cell activation and tolerance by TGF-beta and NFAT. Curr Opin Immunol 19:287–293CrossRefPubMedGoogle Scholar
  34. 34.
    Vukmanovic-Stejic M, Zhang Y, Cook JE et al (2006) Human CD4+ CD25hi Foxp3+ regulatory T cells are derived by rapid turnover of memory populations in vivo. J Clin Invest 116:2423–2433CrossRefPubMedGoogle Scholar
  35. 35.
    Wolf AM, Wolf D, Steurer M et al (2003) Increase of regulatory T cells in the peripheral blood of cancer patients. Clin Cancer Res 9:606–612PubMedGoogle Scholar
  36. 36.
    Wolf D, Wolf AM, Rumpold H et al (2005) The expression of the regulatory T cell-specific forkhead box transcription factor FoxP3 is associated with poor prognosis in ovarian cancer. Clin Cancer Res 11:8326–8331CrossRefPubMedGoogle Scholar
  37. 37.
    Woo EY, Yeh H, Chu CS et al (2002) Cutting edge: regulatory T cells from lung cancer patients directly inhibit autologous T cell proliferation. J Immunol 168:4272–4276PubMedGoogle Scholar
  38. 38.
    Zhang L, Conejo-Garcia JR, Katsaros D et al (2003) Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 348:203–213CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Hiroyuki Suzuki
    • 1
  • Nobuhito Chikazawa
    • 1
  • Takehiko Tasaka
    • 1
  • Junji Wada
    • 1
  • Akio Yamasaki
    • 1
  • Yoshiki Kitaura
    • 1
  • Masae Sozaki
    • 1
  • Masao Tanaka
    • 2
  • Hideya Onishi
    • 1
  • Takashi Morisaki
    • 1
  • Mitsuo Katano
    • 1
    Email author
  1. 1.Department of Cancer Therapy and Research, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
  2. 2.Department of Surgery and Oncology, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan

Personalised recommendations