Gastroenterology
Volume 137, Issue 4 , Pages 1270-1279 , October 2009

Intraepithelial Effector (CD3+)/Regulatory (FoxP3+) T-Cell Ratio Predicts a Clinical Outcome of Human Colon Carcinoma

  • Frank A. Sinicrope

      Affiliations

    • Corresponding Author InformationReprint requests Address requests for reprints to: Frank A. Sinicrope, MD, Mayo Clinic, 200 First Street Southwest, Rochester, Minnesota 55905
    • Miles and Shirley Fiterman Digestive Disease Center, Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota
    • Miles and Shirley Fiterman Digestive Disease Center, Division of Oncology, Mayo Clinic, Rochester, Minnesota
  • ,
  • Rafaela L. Rego

      Affiliations

    • Miles and Shirley Fiterman Digestive Disease Center, Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota
    • Miles and Shirley Fiterman Digestive Disease Center, Division of Oncology, Mayo Clinic, Rochester, Minnesota
  • ,
  • Stephen M. Ansell

      Affiliations

    • Miles and Shirley Fiterman Digestive Disease Center, Division of Hematology, Mayo Clinic, Rochester, Minnesota
  • ,
  • Keith L. Knutson

      Affiliations

    • Miles and Shirley Fiterman Digestive Disease Center, Division of Immunology, Mayo Clinic, Rochester, Minnesota
  • ,
  • Nathan R. Foster

      Affiliations

    • Miles and Shirley Fiterman Digestive Disease Center, Division of Biostatistics, Mayo Clinic, Rochester, Minnesota
  • ,
  • Daniel J. Sargent

      Affiliations

    • Miles and Shirley Fiterman Digestive Disease Center, Division of Biostatistics, Mayo Clinic, Rochester, Minnesota

Received 18 July 2008 ,Accepted 24 June 2009.

References 

  1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2006. CA Cancer J Clin. 2006;56:106–130
  2. Zou W. Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol. 2006;6:295–307
  3. Nishikawa H, Kato T, Tawara I, et al. Accelerated chemically induced tumor development mediated by CD4+CD25+ regulatory T cells in wild-type hosts. Proc Natl Acad Sci U S A. 2005;102:9253–9257
  4. Shimizu J, Yamazaki S, Sakaguchi S. Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol. 1999;163:5211–5218
  5. Ziegler SF. FOXP3: of mice and men. Annu Rev Immunol. 2006;24:209–226
  6. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3 [see comment]. Science. 2003;299:1057–1061
  7. Fontenot JD, Rudensky AY. A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3. Nat Immunol. 2005;6:331–337
  8. Bensinger SJ, Walsh PT, Zhang J, et al. Distinct IL-2 receptor signaling pattern in CD4+CD25+ regulatory T cells. J Immunol. 2004;172:5287–5296
  9. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells [see comment]. Nat Immunol. 2003;4:330–336
  10. Yagi H, Nomura T, Nakamura K, et al. Crucial role of FOXP3 in the development and function of human CD25+CD4+ regulatory T cells. Int Immunol. 2004;16:1643–1656
  11. Brunkow ME, Jeffery EW, Hjerrild KA, et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet. 2001;27:68–73
  12. Curiel TJ, Coukos G, Zou L, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival [see comment]. Nat Med. 2004;10:942–949
  13. Turk MJ, Guevara-Patino JA, Rizzuto GA, et al. Concomitant tumor immunity to a poorly immunogenic melanoma is prevented by regulatory T cells. J Exp Med. 2004;200:771–782
  14. Wolf AM, Wolf D, Steurer M, et al. Increase of regulatory T cells in the peripheral blood of cancer patients. Clin Cancer Res. 2003;9:606–612
  15. Sasada T, Kimura M, Yoshida Y, et al. CD4+CD25+ regulatory T cells in patients with gastrointestinal malignancies: possible involvement of regulatory T cells in disease progression. Cancer. 2003;98:1089–1099
  16. Viguier M, Lemaitre F, Verola O, et al. Foxp3 expressing CD4+CD25(high) regulatory T cells are overrepresented in human metastatic melanoma lymph nodes and inhibit the function of infiltrating T cells. J Immunol. 2004;173:1444–1453
  17. Liyanage UK, Moore TT, Joo HG, et al. Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol. 2002;169:2756–2761
  18. Yu P, Lee Y, Liu W, et al. Intratumor depletion of CD4+ cells unmasks tumor immunogenicity leading to the rejection of late-stage tumors. J Exp Med. 2005;201:779–791
  19. Wolf D, Wolf AM, Rumpold H, et al. The expression of the regulatory T cell-specific forkhead box transcription factor FoxP3 is associated with poor prognosis in ovarian cancer [see comment]. Clin Cancer Res. 2005;11:8326–8331
  20. Bates GJ, Fox SB, Han C, et al. Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse [see comment]. J Clin Oncol. 2006;24:5373–5380
  21. Fu J, Xu D, Liu Z, et al. Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology. 2007;132:2328–2339
  22. Sato E, Olson SH, Ahn J, 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 U S A. 2005;102:18538–18543
  23. Siddiqui SA, Frigola X, Bonne-Annee S, et al. Tumor-infiltrating Foxp3-CD4+CD25+ T cells predict poor survival in renal cell carcinoma. Clin Cancer Res. 2007;13:2075–2081
  24. Yoshioka T, Miyamoto M, Cho Y, 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
  25. Sinicrope FA, Rego RL, Garrity-Park MM, et al. Alterations in cell proliferation and apoptosis in colon cancers with microsatellite instability. Int J Cancer. 2007;120:1232–1238
  26. Guidoboni M, Gafa R, Viel A, et al. Microsatellite instability and high content of activated cytotoxic lymphocytes identify colon cancer patients with a favorable prognosis. Am J Pathol. 2001;159:297–304
  27. Baker K, Zlobec I, Tornillo L, et al. Differential significance of tumour infiltrating lymphocytes in sporadic mismatch repair deficient versus proficient colorectal cancers: a potential role for dysregulation of the transforming growth factor-beta pathway. Eur J Cancer. 2007;43:624–631
  28. Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313:1960–1964
  29. Ionov Y, Peinado MA, Malkhosyan S, et al. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature. 1993;363:558–561
  30. Michael-Robinson JM, Biemer-Huttmann A, Purdie DM, et al. Tumour infiltrating lymphocytes and apoptosis are independent features in colorectal cancer stratified according to microsatellite instability status. Gut. 2001;48:360–366
  31. Popat S, Hubner R, Houlston RS. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol. 2005;23:609–618
  32. Sinicrope FA, Rego RL, Halling KC, et al. Prognostic impact of microsatellite instability and DNA ploidy in human colon carcinoma patients. Gastroenterology. 2006;131:729–737
  33. Allegra CJ, Parr AL, Wold LE, et al. Investigation of the prognostic and predictive value of thymidylate synthase, p53, and Ki-67 in patients with locally advanced colon cancer. J Clin Oncol. 2002;20:1735–1743
  34. O'Connell MJ, Sargent DJ, Windschitl HE, et al. Randomized clinical trial of high-dose levamisole combined with 5-fluorouracil and leucovorin as surgical adjuvant therapy for high-risk colon cancer. Clin Colorectal Cancer. 2006;6:133–139
  35. Halling KC, French AJ, McDonnell SK, et al. Microsatellite instability and 8p allelic imbalance in stage B2 and C colorectal cancers [see comment]. J Natl Cancer Inst. 1999;91:1295–1303
  36. Thibodeau SN, French AJ, Cunningham JM, et al. Microsatellite instability in colorectal cancer: different mutator phenotypes and the principal involvement of hMLH1. Cancer Res. 1998;58:1713–1718
  37. de la Chapelle A. Testing tumors for microsatellite instability. Eur J Hum Genet. 1999;7:407–408
  38. Bluestone JA, Abbas AK. Natural versus adaptive regulatory T cells. Nat Rev Immunol. 2003;3:253–257
  39. Weisenberger DJ, Siegmund KD, Campan M, et al. CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet. 2006;38:787–793
  40. Aaltonen LA, Salovaara R, Kristo P, et al. Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease. N Engl J Med. 1998;338:1481–1487
  41. Cao X, Cai SF, Fehniger TA, et al. Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance. Immunity. 2007;27:635–646
  42. Clarke SL, Betts GJ, Plant A, et al. CD4+CD25+FOXP3+ regulatory T cells suppress anti-tumor immune responses in patients with colorectal cancer. PLoS ONE. 2006;1:e129
  43. Ling KL, Pratap SE, Bates GJ, et al. Increased frequency of regulatory T cells in peripheral blood and tumour infiltrating lymphocytes in colorectal cancer patients. Cancer Immunity. 2007;7:7
  44. O'Connell JB, Maggard MA, Ko CY. Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. J Natl Cancer Inst. 2004;96:1420–1425
  45. Petersen RP, Campa MJ, Sperlazza J, et al. Tumor infiltrating Foxp3+ regulatory T-cells are associated with recurrence in pathologic stage I NSCLC patients. Cancer. 2006;107:2866–2872
  46. Gao Q, Qiu SJ, Fan J, et al. Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol. 2007;25:2586–2593
  47. Yang ZZ, Novak AJ, Ziesmer SC, et al. Attenuation of CD8(+) T-cell function by CD4(+)CD25(+) regulatory T cells in B-cell non-Hodgkin's lymphoma. Cancer Res. 2006;66:10145–10152
  48. Quezada SA, Peggs KS, Curran MA, et al. CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells. J Clin Invest. 2006;116:1935–1945
  49. Petrini B, Wasserman J, Blomgren H, et al. Changes of blood T cell subsets in patients receiving postoperative adjuvant chemotherapy for breast cancer. Eur J Cancer Clin Oncol. 1984;20:1485–1487
  50. Naito Y, Saito K, Shiiba K, et al. CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res. 1998;58:3491–3494
  51. Chiba T, Ohtani H, Mizoi T, 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
  52. Tomsova M, Melichar B, Sedlakova I, et al. Prognostic significance of CD3+ tumor-infiltrating lymphocytes in ovarian carcinoma. Gynecol Oncol. 2008;108:415–420
  53. Takemoto N, Konishi F, Yamashita K, et al. The correlation of microsatellite instability and tumor-infiltrating lymphocytes in hereditary non-polyposis colorectal cancer (HNPCC) and sporadic colorectal cancers: the significance of different types of lymphocyte infiltration. Jpn J Clin Oncol. 2004;34:90–98
  54. Quinn E, Hawkins N, Yip YL, et al. CD103+ intraepithelial lymphocytes--a unique population in microsatellite unstable sporadic colorectal cancer. Eur J Cancer. 2003;39:469–475
  55. Ebert EC, Roberts AI. Lymphokine-activated killing by human intestinal lymphocytes. Cell Immunol. 1993;146:107–116
  56. Golby SJ, Chinyama C, Spencer J. Proliferation of T-cell subsets that contact tumour cells in colorectal cancer. Clin Exp Immunol. 2002;127:85–91
  57. Zhang L, Conejo-Garcia JR, Katsaros D, et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med. 2003;348:203–213
  58. Reiman JM, Kmieciak M, Manjili MH, et al. Tumor immunoediting and immunosculpting pathways to cancer progression. Semin Cancer Biol. 2007;17:275–287
  59. Brandacher G, Perathoner A, Ladurner R, et al. Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer: effect on tumor-infiltrating T cells. Clin Cancer Res. 2006;12:1144–1151
  60. Jass JR, Do KA, Simms LA, et al. Morphology of sporadic colorectal cancer with DNA replication errors [see comment]. Gut. 1998;42:673–679
  61. Schwitalle Y, Kloor M, Eiermann S, et al. Immune response against frameshift-induced neopeptides in HNPCC patients and healthy HNPCC mutation carriers. Gastroenterology. 2008;134:988–997
  62. Baker K, Foulkes WD, Jass JR. MSI-H colorectal cancers preferentially retain and expand intraepithelial lymphocytes rather than peripherally derived CD8+ T cells. Cancer Immunol Immunother. 2009;58:135–144

 Conflicts of interest The authors disclose no conflicts.

 Funding Supported in part by National Cancer Institute grant CA104683-02 (to F.A.S.) and National Cancer Institute core grant CA15083 (to the Mayo Clinic Cancer Center).

PII: S0016-5085(09)01138-X

doi: 10.1053/j.gastro.2009.06.053

Gastroenterology
Volume 137, Issue 4 , Pages 1270-1279 , October 2009