Skip to main content

Advertisement

SpringerLink
Log in

FOXP3+ Tregs: heterogeneous phenotypes and conflicting impacts on survival outcomes in patients with colorectal cancer

  • Interpretive synthesis review article
  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

The tumor microenvironment composites a mixture of immune lymphoid cells, myeloid cells, stromal cells with complex cytokines, as well as numerous lymphovascular vessels. Colorectal cancer (CRC) is a common malignancy and one of the leading causes of tumor-related death in the United States and worldwide. The immune status in the tumor microenvironment contributes to the survival of a patient with CRC. Regulatory T cells (Tregs) are considered a key factor in immune escape and immunotherapy failure among cancer patients. The transcription factor forkhead box P3 (FOXP3) is a crucial intracellular marker and also a key developmental and functional factor for CD4+CD25+ Tregs. Tregs are correlated with survival in various human neoplasms, and elevated proportions of Tregs are usually associated with unfavorable clinical outcomes. However, the role of Tregs in CRC remains controversial. High densities of tumor-infiltrating Tregs in CRC patients are reported to be correlated with worse or better outcomes. And Tregs may not be predictive of prognosis after resection of the primary tumor. The exact explanations for these discordant results remain unclear. The heterogeneous instincts of cell phenotype, gene expression, and functional activities of Tregs may partly contribute this contrasting result. Furthermore, the lack of a robust marker for identifying Tregs or due to the different techniques applied is also account. The Treg-specific demethylated region (TSDR) was recently reported to be a specific epigenetic marker for natural Tregs (nTregs), which can stably express FOXP3. The FOXP3-TSDR demethylation assay may be an promising technique for CRC-related nTregs studies.

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

Similar content being viewed by others

References

  1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64(1):9–29. doi:10.3322/caac.21208.

    Article  PubMed  Google Scholar 

  2. 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(19):1420–5. doi:10.1093/jnci/djh275.

    Article  PubMed  Google Scholar 

  3. Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010;17(6):1471–4. doi:10.1245/s10434-010-0985-4.

    Article  PubMed  Google Scholar 

  4. Wieczorek G, Asemissen A, Model F, Turbachova I, Floess S, Liebenberg V, et al. Quantitative DNA methylation analysis of FOXP3 as a new method for counting regulatory T cells in peripheral blood and solid tissue. Cancer Res. 2009;69(2):599–608. doi:10.1158/0008-5472.can-08-2361.

    Article  CAS  PubMed  Google Scholar 

  5. Sellitto A, Galizia G, De Fanis U, Lieto E, Zamboli A, Orditura M, et al. Behavior of circulating CD4+CD25+Foxp3+ regulatory T cells in colon cancer patients undergoing surgery. J Clin Immunol. 2011;31(6):1095–104. doi:10.1007/s10875-011-9585-8.

    Article  CAS  PubMed  Google Scholar 

  6. Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity. 2005;22(3):329–41. doi:10.1016/j.immuni.2005.01.016.

    Article  CAS  PubMed  Google Scholar 

  7. Shevach EM. Mechanisms of FoxP3+ T regulatory cell-mediated suppression. Immunity. 2009;30(5):636–45. doi:10.1016/j.immuni.2009.04.010.

    Article  CAS  PubMed  Google Scholar 

  8. Wing K, Sakaguchi S. Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat Immunol. 2010;11(1):7–13. doi:10.1038/ni.1818.

    Article  CAS  PubMed  Google Scholar 

  9. Walker MR, Kasprowicz DJ, Gersuk VH, Benard A, Van Landeghen M, Buckner JH, et al. Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+CD25− T cells. J Clin Investig. 2003;112(9):1437–43. doi:10.1172/jci19441.

    Article  CAS  PubMed  Google Scholar 

  10. Zou W. Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer. 2005;5(4):263–74. doi:10.1038/nrc1586.

    Article  CAS  PubMed  Google Scholar 

  11. Sakaguchi S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol. 2005;6(4):345–52. doi:10.1038/ni1178.

    Article  CAS  PubMed  Google Scholar 

  12. Zou W. Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol. 2006;6(4):295–307. doi:10.1038/nri1806.

    Article  CAS  PubMed  Google Scholar 

  13. Yaqub S, Henjum K, Mahic M, Jahnsen FL, Aandahl EM, Bjornbeth BA, et al. Regulatory T cells in colorectal cancer patients suppress anti-tumor immune activity in a COX-2 dependent manner. CII. 2008;57(6):813–21. doi:10.1007/s00262-007-0417-x.

    CAS  PubMed  Google Scholar 

  14. 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(2):186–92. doi:10.1200/jco.2008.18.7229.

    Article  PubMed  Google Scholar 

  15. Jensen HK, Donskov F, Nordsmark M, Marcussen N, von der Maase H. Increased intratumoral FOXP3-positive regulatory immune cells during interleukin-2 treatment in metastatic renal cell carcinoma. Clin Cancer Res. 2009;15(3):1052–8. doi:10.1158/1078-0432.ccr-08-1296.

    Article  CAS  PubMed  Google Scholar 

  16. Zhuo C, Li Z, Xu Y, Wang Y, Li Q, Peng J, et al. Higher FOXP3-TSDR demethylation rates in adjacent normal tissues in patients with colon cancer were associated with worse survival. Mol Cancer. 2014;13(1):153. doi:10.1186/1476-4598-13-153.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  17. Michel S, Benner A, Tariverdian M, Wentzensen N, Hoefler P, Pommerencke T, et al. High density of FOXP3-positive T cells infiltrating colorectal cancers with microsatellite instability. Br J Cancer. 2008;99(11):1867–73. doi:10.1038/sj.bjc.6604756.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Correale P, Rotundo MS, Del Vecchio MT, Remondo C, Migali C, Ginanneschi C, et al. Regulatory (FoxP3 +) T-cell tumor infiltration is a favorable prognostic factor in advanced colon cancer patients undergoing chemo or chemoimmunotherapy. J Immunother. 2010;33(4):435–41. doi:10.1097/CJI.0b013e3181d32f01.

    Article  PubMed  Google Scholar 

  19. Frey DM, Droeser RA, Viehl CT, Zlobec I, Lugli A, Zingg U, et al. High frequency of tumor-infiltrating FOXP3(+) regulatory T cells predicts improved survival in mismatch repair-proficient colorectal cancer patients. Int J Cancer. 2010;126(11):2635–43. doi:10.1002/ijc.24989.

    CAS  PubMed  Google Scholar 

  20. Nosho K, Baba Y, Tanaka N, Shima K, Hayashi M, Meyerhardt JA, et al. Tumour-infiltrating T-cell subsets, molecular changes in colorectal cancer, and prognosis: cohort study and literature review. J Pathol. 2010;222(4):350–66. doi:10.1002/path.2774.

    Article  PubMed Central  PubMed  Google Scholar 

  21. Lee WS, Park S, Lee WY, Yun SH, Chun HK. Clinical impact of tumor-infiltrating lymphocytes for survival in stage II colon cancer. Cancer. 2010;116(22):5188–99. doi:10.1002/cncr.25293.

    Article  PubMed  Google Scholar 

  22. Tosolini M, Kirilovsky A, Mlecnik B, Fredriksen T, Mauger S, Bindea G, et al. Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer. Cancer Res. 2011;71(4):1263–71. doi:10.1158/0008-5472.can-10-2907.

    Article  CAS  PubMed  Google Scholar 

  23. Sinicrope FA, Rego RL, Ansell SM, Knutson KL, Foster NR, Sargent DJ. Intraepithelial effector (CD3 +)/regulatory (FoxP3 +) T-cell ratio predicts a clinical outcome of human colon carcinoma. Gastroenterology. 2009;137(4):1270–9. doi:10.1053/j.gastro.2009.06.053.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Suzuki H, Chikazawa N, Tasaka T, Wada J, Yamasaki A, Kitaura Y, et al. Intratumoral CD8(+) T/FOXP3 (+) cell ratio is a predictive marker for survival in patients with colorectal cancer. CII. 2010;59(5):653–61. doi:10.1007/s00262-009-0781-9.

    CAS  PubMed  Google Scholar 

  25. Gershon RK, Kondo K. Cell interactions in the induction of tolerance: the role of thymic lymphocytes. Immunology. 1970;18(5):723–37.

    PubMed Central  CAS  PubMed  Google Scholar 

  26. Fujimoto S, Greene M, Sehon AH. Immunosuppressor T cells in tumor bearing host. Immunol Commun. 1975;4(3):201–17.

    CAS  PubMed  Google Scholar 

  27. North RJ, Bursuker I. Generation and decay of the immune response to a progressive fibrosarcoma. I. Ly-1+2− suppressor T cells down-regulate the generation of Ly-1−2+ effector T cells. J Exp Med. 1984;159(5):1295–311.

    Article  CAS  PubMed  Google Scholar 

  28. Berendt MJ, North RJ. T-cell-mediated suppression of anti-tumor immunity. An explanation for progressive growth of an immunogenic tumor. J Exp Med. 1980;151(1):69–80.

    Article  CAS  PubMed  Google Scholar 

  29. Bursuker I, North RJ. Generation and decay of the immune response to a progressive fibrosarcoma. II. Failure to demonstrate postexcision immunity after the onset of T cell-mediated suppression of immunity. J Exp Med. 1984;159(5):1312–21.

    Article  CAS  PubMed  Google Scholar 

  30. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. 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. 1995;155(3):1151–64.

    CAS  PubMed  Google Scholar 

  31. Levings MK, Sangregorio R, Roncarolo MG. Human CD25(+)CD4(+) t regulatory cells suppress naive and memory T cell proliferation and can be expanded in vitro without loss of function. J Exp Med. 2001;193(11):1295–302.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Jonuleit H, Schmitt E, Stassen M, Tuettenberg A, Knop J, Enk AH. Identification and functional characterization of human CD4(+)CD25(+) T cells with regulatory properties isolated from peripheral blood. J Exp Med. 2001;193(11):1285–94.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Dieckmann D, Plottner H, Berchtold S, Berger T, Schuler G. Ex vivo isolation and characterization of CD4(+)CD25(+) T cells with regulatory properties from human blood. J Exp Med. 2001;193(11):1303–10.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Ng WF, Duggan PJ, Ponchel F, Matarese G, Lombardi G, Edwards AD, et al. Human CD4(+)CD25(+) cells: a naturally occurring population of regulatory T cells. Blood. 2001;98(9):2736–44.

    Article  CAS  PubMed  Google Scholar 

  35. Roncador G, Brown PJ, Maestre L, Hue S, Martinez-Torrecuadrada JL, Ling KL, et al. Analysis of FOXP3 protein expression in human CD4+CD25 +regulatory T cells at the single-cell level. Eur J Immunol. 2005;35(6):1681–91. doi:10.1002/eji.200526189.

    Article  CAS  PubMed  Google Scholar 

  36. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299(5609):1057–61. doi:10.1126/science.1079490.

    Article  CAS  PubMed  Google Scholar 

  37. Liu W, Putnam AL, Xu-Yu Z, Szot GL, Lee MR, Zhu S, et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med. 2006;203(7):1701–11. doi:10.1084/jem.20060772.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Seddiki N, Santner-Nanan B, Martinson J, Zaunders J, Sasson S, Landay A, et al. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J Exp Med. 2006;203(7):1693–700. doi:10.1084/jem.20060468.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Putnam AL, Brusko TM, Lee MR, Liu W, Szot GL, Ghosh T, et al. Expansion of human regulatory T-cells from patients with type 1 diabetes. Diabetes. 2009;58(3):652–62. doi:10.2337/db08-1168.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Miyara M, Yoshioka Y, Kitoh A, Shima T, Wing K, Niwa A, et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity. 2009;30(6):899–911. doi:10.1016/j.immuni.2009.03.019.

    Article  CAS  PubMed  Google Scholar 

  41. Sakaguchi S, Miyara M, Costantino CM, Hafler DA. FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol. 2010;10(7):490–500. doi:10.1038/nri2785.

    Article  CAS  PubMed  Google Scholar 

  42. Baecher-Allan C, Wolf E, Hafler DA. MHC class II expression identifies functionally distinct human regulatory T cells. J Immunol. 2006;176(8):4622–31.

    Article  CAS  PubMed  Google Scholar 

  43. Ito T, Hanabuchi S, Wang YH, Park WR, Arima K, Bover L, et al. Two functional subsets of FOXP3+ regulatory T cells in human thymus and periphery. Immunity. 2008;28(6):870–80. doi:10.1016/j.immuni.2008.03.018.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Miyara M, Sakaguchi S. Human FoxP3(+)CD4(+) regulatory T cells: their knowns and unknowns. Immunol Cell Biol. 2011;89(3):346–51. doi:10.1038/icb.2010.137.

    Article  CAS  PubMed  Google Scholar 

  45. Osorio F, LeibundGut-Landmann S, Lochner M, Lahl K, Sparwasser T, Eberl G, et al. DC activated via dectin-1 convert Treg into IL-17 producers. Eur J Immunol. 2008;38(12):3274–81. doi:10.1002/eji.200838950.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Li L, Kim J, Boussiotis VA. IL-1beta-mediated signals preferentially drive conversion of regulatory T cells but not conventional T cells into IL-17-producing cells. J Immunol. 2010;185(7):4148–53. doi:10.4049/jimmunol.1001536.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Li L, Patsoukis N, Petkova V, Boussiotis VA. Runx1 and Runx3 are involved in the generation and function of highly suppressive IL-17-producing T regulatory cells. PLoS ONE. 2012;7(9):e45115. doi:10.1371/journal.pone.0045115.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Blatner NR, Mulcahy MF, Dennis KL, Scholtens D, Bentrem DJ, Phillips JD, et al. Expression of RORgammat marks a pathogenic regulatory T cell subset in human colon cancer. Sci Transl Med. 2012;4(164):164ra59. doi:10.1126/scitranslmed.3004566.

    Google Scholar 

  49. Groux H, O’Garra A, Bigler M, Rouleau M, Antonenko S, de Vries JE, et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature. 1997;389(6652):737–42. doi:10.1038/39614.

    Article  CAS  PubMed  Google Scholar 

  50. Dhodapkar MV, Steinman RM, Krasovsky J, Munz C, Bhardwaj N. Antigen-specific inhibition of effector T cell function in humans after injection of immature dendritic cells. J Exp Med. 2001;193(2):233–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Gabrilovich D. Mechanisms and functional significance of tumour-induced dendritic-cell defects. Nat Rev Immunol. 2004;4(12):941–52. doi:10.1038/nri1498.

    Article  CAS  PubMed  Google Scholar 

  52. Chakraborty NG, Chattopadhyay S, Mehrotra S, Chhabra A, Mukherji B. Regulatory T-cell response and tumor vaccine-induced cytotoxic T lymphocytes in human melanoma. Hum Immunol. 2004;65(8):794–802. doi:10.1016/j.humimm.2004.05.012.

    Article  CAS  PubMed  Google Scholar 

  53. Weiner HL. Induction and mechanism of action of transforming growth factor-beta-secreting Th3 regulatory cells. Immunol Rev. 2001;182:207–14.

    Article  CAS  PubMed  Google Scholar 

  54. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133(5):775–87. doi:10.1016/j.cell.2008.05.009.

    Article  CAS  PubMed  Google Scholar 

  55. Allan SE, Crome SQ, Crellin NK, Passerini L, Steiner TS, Bacchetta R, et al. Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production. Int Immunol. 2007;19(4):345–54. doi:10.1093/intimm/dxm014.

    Article  CAS  PubMed  Google Scholar 

  56. Ohkura N, Hamaguchi M, Morikawa H, Sugimura K, Tanaka A, Ito Y, et al. T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity. 2012;37(5):785–99. doi:10.1016/j.immuni.2012.09.010.

    Article  CAS  PubMed  Google Scholar 

  57. Picca CC, Larkin J 3rd, Boesteanu A, Lerman MA, Rankin AL, Caton AJ. Role of TCR specificity in CD4+CD25+ regulatory T-cell selection. Immunol Rev. 2006;212:74–85. doi:10.1111/j.0105-2896.2006.00416.x.

    Article  PubMed  Google Scholar 

  58. Nishikawa H, Sakaguchi S. Regulatory T cells in cancer immunotherapy. Curr Opin Immunol. 2014;27c:1–7. doi:10.1016/j.coi.2013.12.005.

    Article  CAS  Google Scholar 

  59. Seddiki N, Santner-Nanan B, Tangye SG, Alexander SI, Solomon M, Lee S, et al. Persistence of naive CD45RA+ regulatory T cells in adult life. Blood. 2006;107(7):2830–8. doi:10.1182/blood-2005-06-2403.

    Article  CAS  PubMed  Google Scholar 

  60. Fritzsching B, Oberle N, Pauly E, Geffers R, Buer J, Poschl J, et al. Naive regulatory T cells: a novel subpopulation defined by resistance toward CD95L-mediated cell death. Blood. 2006;108(10):3371–8. doi:10.1182/blood-2006-02-005660.

    Article  CAS  PubMed  Google Scholar 

  61. Valmori D, Merlo A, Souleimanian NE, Hesdorffer CS, Ayyoub M. A peripheral circulating compartment of natural naive CD4 Tregs. J Clin Investig. 2005;115(7):1953–62. doi:10.1172/jci23963.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  62. Hoffmann P, Eder R, Boeld TJ, Doser K, Piseshka B, Andreesen R, et al. Only the CD45RA+ subpopulation of CD4+ CD25high T cells gives rise to homogeneous regulatory T-cell lines upon in vitro expansion. Blood. 2006;108(13):4260–7. doi:10.1182/blood-2006-06-027409.

    Article  CAS  PubMed  Google Scholar 

  63. von Boehmer H. Mechanisms of suppression by suppressor T cells. Nat Immunol. 2005;6(4):338–44. doi:10.1038/ni1180.

    Article  CAS  Google Scholar 

  64. Koch MA, Tucker-Heard G, Perdue NR, Killebrew JR, Urdahl KB, Campbell DJ. The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat Immunol. 2009;10(6):595–602. doi:10.1038/ni.1731.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  65. Zheng Y, Chaudhry A, Kas A, deRoos P, Kim JM, Chu TT, et al. Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. Nature. 2009;458(7236):351–6. doi:10.1038/nature07674.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  66. Chaudhry A, Rudra D, Treuting P, Samstein RM, Liang Y, Kas A, et al. CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science. 2009;326(5955):986–91. doi:10.1126/science.1172702.

    Article  CAS  PubMed  Google Scholar 

  67. Chung Y, Tanaka S, Chu F, Nurieva RI, Martinez GJ, Rawal S, et al. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat Med. 2011;17(8):983–8. doi:10.1038/nm.2426.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  68. Linterman MA, Pierson W, Lee SK, Kallies A, Kawamoto S, Rayner TF, et al. Foxp3+ follicular regulatory T cells control the germinal center response. Nat Med. 2011;17(8):975–82. doi:10.1038/nm.2425.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  69. Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science. 2008;322(5899):271–5. doi:10.1126/science.1160062.

    Article  CAS  PubMed  Google Scholar 

  70. Pandiyan P, Zheng L, Ishihara S, Reed J, Lenardo MJ. CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T cells. Nat Immunol. 2007;8(12):1353–62. doi:10.1038/ni1536.

    Article  CAS  PubMed  Google Scholar 

  71. Chen YT, Scanlan MJ, Sahin U, Tureci O, Gure AO, Tsang S, et al. A testicular antigen aberrantly expressed in human cancers detected by autologous antibody screening. Proc Natl Acad Sci USA. 1997;94(5):1914–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  72. Danke NA, Koelle DM, Yee C, Beheray S, Kwok WW. Autoreactive T cells in healthy individuals. J Immunol. 2004;172(10):5967–72.

    Article  CAS  PubMed  Google Scholar 

  73. Nishikawa H, Jager E, Ritter G, Old LJ, Gnjatic S. CD4+CD25+ regulatory T cells control the induction of antigen-specific CD4+ helper T cell responses in cancer patients. Blood. 2005;106(3):1008–11. doi:10.1182/blood-2005-02-0607.

    Article  CAS  PubMed  Google Scholar 

  74. Nishikawa H, Qian F, Tsuji T, Ritter G, Old LJ, Gnjatic S, et al. Influence of CD4+CD25+ regulatory T cells on low/high-avidity CD4+ T cells following peptide vaccination. J Immunol. 2006;176(10):6340–6.

    Article  CAS  PubMed  Google Scholar 

  75. Schott AK, Pries R, Wollenberg B. Permanent up-regulation of regulatory T-lymphocytes in patients with head and neck cancer. Int J Mol Med. 2010;26(1):67–75.

    CAS  PubMed  Google Scholar 

  76. Watanabe MA, Oda JM, Amarante MK, Cesar Voltarelli J. Regulatory T cells and breast cancer: implications for immunopathogenesis. Cancer Metastasis Rev. 2010;29(4):569–79. doi:10.1007/s10555-010-9247-y.

    Article  CAS  PubMed  Google Scholar 

  77. 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(51):18538–43. doi:10.1073/pnas.0509182102.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  78. Wicherek L, Jozwicki W, Windorbska W, Roszkowski K, Lukaszewska E, Wisniewski M, et al. Analysis of Treg cell population alterations in the peripheral blood of patients treated surgically for ovarian cancer—a preliminary report. Am J Reprod Immunol. 2011;66(5):444–50. doi:10.1111/j.1600-0897.2011.01024.x.

    Article  PubMed  Google Scholar 

  79. Suzuki K, Kadota K, Sima CS, Nitadori J, Rusch VW, Travis WD, et al. Clinical impact of immune microenvironment in stage I lung adenocarcinoma: tumor interleukin-12 receptor beta2 (IL-12Rbeta2), IL-7R, and stromal FoxP3/CD3 ratio are independent predictors of recurrence. J Clin Oncol. 2013;31(4):490–8. doi:10.1200/jco.2012.45.2052.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  80. Cabrera R, Ararat M, Xu Y, Brusko T, Wasserfall C, Atkinson MA, et al. Immune modulation of effector CD4+ and regulatory T cell function by sorafenib in patients with hepatocellular carcinoma. CII. 2013;62(4):737–46. doi:10.1007/s00262-012-1380-8.

    CAS  PubMed  Google Scholar 

  81. Shevchenko I, Karakhanova S, Soltek S, Link J, Bayry J, Werner J, et al. Low-dose gemcitabine depletes regulatory T cells and improves survival in the orthotopic Panc02 model of pancreatic cancer. Int J Cancer. 2013;133(1):98–107. doi:10.1002/ijc.27990.

    Article  CAS  PubMed  Google Scholar 

  82. Yoshii M, Tanaka H, Ohira M, Muguruma K, Iwauchi T, Lee T, et al. Expression of Forkhead box P3 in tumour cells causes immunoregulatory function of signet ring cell carcinoma of the stomach. Br J Cancer. 2012;106(10):1668–74. doi:10.1038/bjc.2012.141.

    PubMed Central  CAS  PubMed  Google Scholar 

  83. de Vries IJ, Castelli C, Huygens C, Jacobs JF, Stockis J, Schuler-Thurner B, et al. Frequency of circulating Tregs with demethylated FOXP3 intron 1 in melanoma patients receiving tumor vaccines and potentially Treg-depleting agents. Clin Cancer Res. 2011;17(4):841–8. doi:10.1158/1078-0432.ccr-10-2227.

    Article  PubMed  CAS  Google Scholar 

  84. Floess S, Freyer J, Siewert C, Baron U, Olek S, Polansky J, et al. Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol. 2007;5(2):e38. doi:10.1371/journal.pbio.0050038.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  85. Kryczek I, Wu K, Zhao E, Wei S, Vatan L, Szeliga W, et al. IL-17+ regulatory T cells in the microenvironments of chronic inflammation and cancer. J Immunol. 2011;186(7):4388–95. doi:10.4049/jimmunol.1003251.

    Article  CAS  PubMed  Google Scholar 

  86. Pesenacker AM, Bending D, Ursu S, Wu Q, Nistala K, Wedderburn LR. CD161 defines the subset of FoxP3+ T cells capable of producing pro-inflammatory cytokines. Blood. 2013;. doi:10.1182/blood-2012-08-443473.

    PubMed Central  PubMed  Google Scholar 

  87. Erdman SE, Rao VP, Poutahidis T, Ihrig MM, Ge Z, Feng Y, et al. CD4(+)CD25(+) regulatory lymphocytes require interleukin 10 to interrupt colon carcinogenesis in mice. Cancer Res. 2003;63(18):6042–50.

    CAS  PubMed  Google Scholar 

  88. Erdman SE, Sohn JJ, Rao VP, Nambiar PR, Ge Z, Fox JG, et al. CD4+CD25+ regulatory lymphocytes induce regression of intestinal tumors in ApcMin/+ mice. Cancer Res. 2005;65(10):3998–4004. doi:10.1158/0008-5472.can-04-3104.

    Article  CAS  PubMed  Google Scholar 

  89. Terzic J, Grivennikov S, Karin E, Karin M. Inflammation and colon cancer. Gastroenterology. 2010;138(6):2101e5–2114e5. doi:10.1053/j.gastro.2010.01.058.

    Article  CAS  Google Scholar 

  90. Izcue A, Coombes JL, Powrie F. Regulatory T cells suppress systemic and mucosal immune activation to control intestinal inflammation. Immunol Rev. 2006;212:256–71. doi:10.1111/j.0105-2896.2006.00423.x.

    Article  CAS  PubMed  Google Scholar 

  91. Newberry RD, Lorenz RG. Organizing a mucosal defense. Immunol Rev. 2005;206:6–21. doi:10.1111/j.0105-2896.2005.00282.x.

    Article  CAS  PubMed  Google Scholar 

  92. Li L, Boussiotis VA. The role of IL-17-producing Foxp3+CD4+ T cells in inflammatory bowel disease and colon cancer. Clin Immunol. 2013;148(2):246–53. doi:10.1016/j.clim.2013.05.003.

    Article  CAS  PubMed  Google Scholar 

  93. Maul J, Loddenkemper C, Mundt P, Berg E, Giese T, Stallmach A, et al. Peripheral and intestinal regulatory CD4+ CD25(high) T cells in inflammatory bowel disease. Gastroenterology. 2005;128(7):1868–78.

    Article  CAS  PubMed  Google Scholar 

  94. Kanai T, Nemoto Y, Kamada N, Totsuka T, Hisamatsu T, Watanabe M, et al. Homeostatic (IL-7) and effector (IL-17) cytokines as distinct but complementary target for an optimal therapeutic strategy in inflammatory bowel disease. Curr Opin Gastroenterol. 2009;25(4):306–13. doi:10.1097/MOG.0b013e32832bc627.

    Article  CAS  PubMed  Google Scholar 

  95. Eastaff-Leung N, Mabarrack N, Barbour A, Cummins A, Barry S. Foxp3+ regulatory T cells, Th17 effector cells, and cytokine environment in inflammatory bowel disease. J Clin Immunol. 2010;30(1):80–9. doi:10.1007/s10875-009-9345-1.

    Article  CAS  PubMed  Google Scholar 

  96. Witowski J, Ksiazek K, Jorres A. Interleukin-17: a mediator of inflammatory responses. CMLS. 2004;61(5):567–79. doi:10.1007/s00018-003-3228-z.

    Article  CAS  PubMed  Google Scholar 

  97. Lee E, Trepicchio WL, Oestreicher JL, Pittman D, Wang F, Chamian F, et al. Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. J Exp Med. 2004;199(1):125–30. doi:10.1084/jem.20030451.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  98. Weaver CT, Harrington LE, Mangan PR, Gavrieli M, Murphy KM. Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity. 2006;24(6):677–88. doi:10.1016/j.immuni.2006.06.002.

    Article  CAS  PubMed  Google Scholar 

  99. Weaver CT, Hatton RD, Mangan PR, Harrington LE. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol. 2007;25:821–52. doi:10.1146/annurev.immunol.25.022106.141557.

    Article  CAS  PubMed  Google Scholar 

  100. Liu J, Duan Y, Cheng X, Chen X, Xie W, Long H, et al. IL-17 is associated with poor prognosis and promotes angiogenesis via stimulating VEGF production of cancer cells in colorectal carcinoma. Biochem Biophys Res Commun. 2011;407(2):348–54. doi:10.1016/j.bbrc.2011.03.021.

    Article  CAS  PubMed  Google Scholar 

  101. Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell. 2006;126(6):1121–33. doi:10.1016/j.cell.2006.07.035.

    Article  CAS  PubMed  Google Scholar 

  102. Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity. 2006;24(2):179–89. doi:10.1016/j.immuni.2006.01.001.

    Article  CAS  PubMed  Google Scholar 

  103. Zhou L, Lopes JE, Chong MM, Ivanov II, Min R, Victora GD, et al. TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature. 2008;453(7192):236–40. doi:10.1038/nature06878.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  104. Ziegler SF. FOXP3: not just for regulatory T cells anymore. Eur J Immunol. 2007;37(1):21–3. doi:10.1002/eji.200636929.

    Article  CAS  PubMed  Google Scholar 

  105. d’Hennezel E, Piccirillo CA. Analysis of human FOXP3+ Treg cells phenotype and function. Methods Mol Biol. 2011;707:199–218. doi:10.1007/978-1-61737-979-6_13.

    Article  PubMed  CAS  Google Scholar 

  106. Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12(4):298–306. doi:10.1038/nrc3245.

    Article  CAS  PubMed  Google Scholar 

  107. Thornton AM, Korty PE, Tran DQ, Wohlfert EA, Murray PE, Belkaid Y, et al. Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J Immunol. 2010;184(7):3433–41. doi:10.4049/jimmunol.0904028.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  108. Akimova T, Beier UH, Wang L, Levine MH, Hancock WW. Helios expression is a marker of T cell activation and proliferation. PLoS ONE. 2011;6(8):e24226. doi:10.1371/journal.pone.0024226.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  109. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9(6):669–76. doi:10.1038/nm0603-669.

    Article  CAS  PubMed  Google Scholar 

  110. Glinka Y, Prud’homme GJ. Neuropilin-1 is a receptor for transforming growth factor beta-1, activates its latent form, and promotes regulatory T cell activity. J Leukoc Biol. 2008;84(1):302–10. doi:10.1189/jlb.0208090.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  111. Yadav M, Louvet C, Davini D, Gardner JM, Martinez-Llordella M, Bailey-Bucktrout S, et al. Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo. J Exp Med. 2012;209(10):1713–22. doi:10.1084/jem.20120822, s1–s19.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  112. Weiss JM, Bilate AM, Gobert M, Ding Y, Curotto de Lafaille MA, Parkhurst CN, et al. Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+ T reg cells. J Exp Med. 2012;209(10):1723–42. doi:10.1084/jem.20120914, s1.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  113. Povoleri GA, Scotta C, Nova-Lamperti EA, John S, Lombardi G, Afzali B. Thymic versus induced regulatory T cells—who regulates the regulators? Front Immunol. 2013;4:169. doi:10.3389/fimmu.2013.00169.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  114. Meng HX, Cao Y, Zhang SQ, Bi ZG, Yamakawa M. Distribution of regulatory T cells and interaction with dendritic cells in the synovium of rheumatoid arthritis. Scand J Rheumatol. 2012;41(6):413–20. doi:10.3109/03009742.2012.696135.

    Article  PubMed  Google Scholar 

  115. Eckhardt F, Lewin J, Cortese R, Rakyan VK, Attwood J, Burger M, et al. DNA methylation profiling of human chromosomes 6, 20 and 22. Nat Genet. 2006;38(12):1378–85. doi:10.1038/ng1909.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  116. Baron U, Turbachova I, Hellwag A, Eckhardt F, Berlin K, Hoffmuller U, et al. DNA methylation analysis as a tool for cell typing. Epigenetics. 2006;1(1):55–60.

    Article  PubMed  Google Scholar 

  117. Baron U, Floess S, Wieczorek G, Baumann K, Grutzkau A, Dong J, et al. DNA demethylation in the human FOXP3 locus discriminates regulatory T cells from activated FOXP3(+) conventional T cells. Eur J Immunol. 2007;37(9):2378–89. doi:10.1002/eji.200737594.

    Article  CAS  PubMed  Google Scholar 

  118. Toker A, Engelbert D, Garg G, Polansky JK, Floess S, Miyao T, et al. Active demethylation of the Foxp3 locus leads to the generation of stable regulatory T cells within the thymus. J Immunol. 2013;. doi:10.4049/jimmunol.1203473.

    PubMed  Google Scholar 

  119. Ohkura N, Kitagawa Y, Sakaguchi S. Development and maintenance of regulatory T cells. Immunity. 2013;38(3):414–23. doi:10.1016/j.immuni.2013.03.002.

    Article  CAS  PubMed  Google Scholar 

  120. Tatura R, Zeschnigk M, Adamzik M, Probst-Kepper M, Buer J, Kehrmann J. Quantification of regulatory T cells in septic patients by real-time PCR-based methylation assay and flow cytometry. PLoS ONE. 2012;7(11):e49962. doi:10.1371/journal.pone.0049962.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  121. McClymont SA, Putnam AL, Lee MR, Esensten JH, Liu W, Hulme MA, et al. Plasticity of human regulatory T cells in healthy subjects and patients with type 1 diabetes. J Immunol. 2011;186(7):3918–26. doi:10.4049/jimmunol.1003099.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  122. Schwarzer A, Wolf B, Fisher JL, Schwaab T, Olek S, Baron U, et al. Regulatory T-Cells and associated pathways in metastatic renal cell carcinoma (mRCC) patients undergoing DC-vaccination and cytokine-therapy. PLoS ONE. 2012;7(10):e46600. doi:10.1371/journal.pone.0046600.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  123. Appel H, Wu P, Scheer R, Kedor C, Sawitzki B, Thiel A, et al. Synovial and peripheral blood CD4+FoxP3+ T cells in spondyloarthritis. J Rheumatol. 2011;38(11):2445–51. doi:10.3899/jrheum.110377.

    Article  CAS  PubMed  Google Scholar 

  124. Peiseler M, Sebode M, Franke B, Wortmann F, Schwinge D, Quaas A, et al. FOXP3+ regulatory T cells in autoimmune hepatitis are fully functional and not reduced in frequency. J Hepatol. 2012;57(1):125–32. doi:10.1016/j.jhep.2012.02.029.

    Article  CAS  PubMed  Google Scholar 

  125. Barzaghi F, Passerini L, Gambineri E, Ciullini Mannurita S, Cornu T, Kang ES, et al. Demethylation analysis of the FOXP3 locus shows quantitative defects of regulatory T cells in IPEX-like syndrome. J Autoimmun. 2012;38(1):49–58. doi:10.1016/j.jaut.2011.12.009.

    Article  CAS  PubMed  Google Scholar 

  126. Alexander T, Sattler A, Templin L, Kohler S, Gross C, Meisel A, et al. Foxp3+Helios+ regulatory T cells are expanded in active systemic lupus erythematosus. Ann Rheum Dis. 2013;72(9):1549–58. doi:10.1136/annrheumdis-2012-202216.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Natural Science Foundation of China (No. 81372646 to Cai S. J. and No. 81101586 and 81201836 to Li D. W.), Shanghai International Science and Technology Cooperation Fund (No. 12410707700 to Xu Y.).

Conflict of interest

The authors have no conflicts of interest to disclose.

Author information

Author notes

    Authors and Affiliations

    1. Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong-an Road, Shanghai, 20032, People’s Republic of China

      Changhua Zhuo, Ye Xu, Qingguo Li, Liyong Huang, Dawei Li & Sanjun Cai

    2. Department of Oncology, Shanghai Medical College, Fudan University, No. 270 Dong-an Road, Shanghai, 20032, People’s Republic of China

      Changhua Zhuo, Ye Xu, Qingguo Li, Liyong Huang, Dawei Li & Sanjun Cai

    3. Department of Surgical Oncology, Fujian Provincial Cancer Hospital, Teaching Hospital of Fujian Medical University, No. 420 Fu-ma Road, Fuzhou, 350014, People’s Republic of China

      Changhua Zhuo & Mingang Ying

    4. Key Laboratory of Molecular Virology and Immunology, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, No. 320 Yue-yang Road, Shanghai, 20031, People’s Republic of China

      Bin Li

    Authors
    1. Changhua Zhuo
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Ye Xu
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Mingang Ying
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Qingguo Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Liyong Huang
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Dawei Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Sanjun Cai
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Bin Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Sanjun Cai or Bin Li.

    Additional information

    Changhua Zhuo and Ye Xu have contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Zhuo, C., Xu, Y., Ying, M. et al. FOXP3+ Tregs: heterogeneous phenotypes and conflicting impacts on survival outcomes in patients with colorectal cancer. Immunol Res 61, 338–347 (2015). https://doi.org/10.1007/s12026-014-8616-y

    Download citation

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s12026-014-8616-y

    Keywords

    Search

    Navigation