Advertisement

Immunologic Research

, Volume 61, Issue 3, pp 338–347 | Cite as

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

  • Changhua Zhuo
  • Ye Xu
  • Mingang Ying
  • Qingguo Li
  • Liyong Huang
  • Dawei Li
  • Sanjun Cai
  • Bin Li
Interpretive synthesis review article

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.

Keywords

Regulatory T cells (Tregs) Colorectal cancer (CRC) Transcription factor forkhead box P3 (FOXP3) Treg-specific demethylated region (TSDR) Epigenetic phenotype Survival outcome 

Notes

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.

References

  1. 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.PubMedCrossRefGoogle Scholar
  2. 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.PubMedCrossRefGoogle Scholar
  3. 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.PubMedCrossRefGoogle Scholar
  4. 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.PubMedCrossRefGoogle Scholar
  5. 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.PubMedCrossRefGoogle Scholar
  6. 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.PubMedCrossRefGoogle Scholar
  7. 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.PubMedCrossRefGoogle Scholar
  8. 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.PubMedCrossRefGoogle Scholar
  9. 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.PubMedCrossRefGoogle Scholar
  10. 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.PubMedCrossRefGoogle Scholar
  11. 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.PubMedCrossRefGoogle Scholar
  12. 12.
    Zou W. Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol. 2006;6(4):295–307. doi: 10.1038/nri1806.PubMedCrossRefGoogle Scholar
  13. 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.PubMedGoogle Scholar
  14. 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.PubMedCrossRefGoogle Scholar
  15. 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.PubMedCrossRefGoogle Scholar
  16. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 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.PubMedCrossRefGoogle Scholar
  19. 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.PubMedGoogle Scholar
  20. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 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.PubMedCrossRefGoogle Scholar
  22. 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.PubMedCrossRefGoogle Scholar
  23. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 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.PubMedGoogle Scholar
  25. 25.
    Gershon RK, Kondo K. Cell interactions in the induction of tolerance: the role of thymic lymphocytes. Immunology. 1970;18(5):723–37.PubMedCentralPubMedGoogle Scholar
  26. 26.
    Fujimoto S, Greene M, Sehon AH. Immunosuppressor T cells in tumor bearing host. Immunol Commun. 1975;4(3):201–17.PubMedGoogle Scholar
  27. 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.PubMedCrossRefGoogle Scholar
  28. 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.PubMedCrossRefGoogle Scholar
  29. 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.PubMedCrossRefGoogle Scholar
  30. 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.PubMedGoogle Scholar
  31. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 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.PubMedCrossRefGoogle Scholar
  35. 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.PubMedCrossRefGoogle Scholar
  36. 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.PubMedCrossRefGoogle Scholar
  37. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  38. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  39. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  40. 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.PubMedCrossRefGoogle Scholar
  41. 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.PubMedCrossRefGoogle Scholar
  42. 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.PubMedCrossRefGoogle Scholar
  43. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  44. 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.PubMedCrossRefGoogle Scholar
  45. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  46. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  47. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  48. 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. 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.PubMedCrossRefGoogle Scholar
  50. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  51. 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.PubMedCrossRefGoogle Scholar
  52. 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.PubMedCrossRefGoogle Scholar
  53. 53.
    Weiner HL. Induction and mechanism of action of transforming growth factor-beta-secreting Th3 regulatory cells. Immunol Rev. 2001;182:207–14.PubMedCrossRefGoogle Scholar
  54. 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.PubMedCrossRefGoogle Scholar
  55. 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.PubMedCrossRefGoogle Scholar
  56. 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.PubMedCrossRefGoogle Scholar
  57. 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.PubMedCrossRefGoogle Scholar
  58. 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.CrossRefGoogle Scholar
  59. 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.PubMedCrossRefGoogle Scholar
  60. 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.PubMedCrossRefGoogle Scholar
  61. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  62. 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.PubMedCrossRefGoogle Scholar
  63. 63.
    von Boehmer H. Mechanisms of suppression by suppressor T cells. Nat Immunol. 2005;6(4):338–44. doi: 10.1038/ni1180.CrossRefGoogle Scholar
  64. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  65. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  66. 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.PubMedCrossRefGoogle Scholar
  67. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  68. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  69. 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.PubMedCrossRefGoogle Scholar
  70. 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.PubMedCrossRefGoogle Scholar
  71. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  72. 72.
    Danke NA, Koelle DM, Yee C, Beheray S, Kwok WW. Autoreactive T cells in healthy individuals. J Immunol. 2004;172(10):5967–72.PubMedCrossRefGoogle Scholar
  73. 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.PubMedCrossRefGoogle Scholar
  74. 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.PubMedCrossRefGoogle Scholar
  75. 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.PubMedGoogle Scholar
  76. 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.PubMedCrossRefGoogle Scholar
  77. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  78. 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.PubMedCrossRefGoogle Scholar
  79. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  80. 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.PubMedGoogle Scholar
  81. 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.PubMedCrossRefGoogle Scholar
  82. 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.PubMedCentralPubMedGoogle Scholar
  83. 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.PubMedCrossRefGoogle Scholar
  84. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  85. 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.PubMedCrossRefGoogle Scholar
  86. 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.PubMedCentralPubMedGoogle Scholar
  87. 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.PubMedGoogle Scholar
  88. 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.PubMedCrossRefGoogle Scholar
  89. 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.CrossRefGoogle Scholar
  90. 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.PubMedCrossRefGoogle Scholar
  91. 91.
    Newberry RD, Lorenz RG. Organizing a mucosal defense. Immunol Rev. 2005;206:6–21. doi: 10.1111/j.0105-2896.2005.00282.x.PubMedCrossRefGoogle Scholar
  92. 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.PubMedCrossRefGoogle Scholar
  93. 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.PubMedCrossRefGoogle Scholar
  94. 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.PubMedCrossRefGoogle Scholar
  95. 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.PubMedCrossRefGoogle Scholar
  96. 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.PubMedCrossRefGoogle Scholar
  97. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  98. 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.PubMedCrossRefGoogle Scholar
  99. 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.PubMedCrossRefGoogle Scholar
  100. 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.PubMedCrossRefGoogle Scholar
  101. 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.PubMedCrossRefGoogle Scholar
  102. 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.PubMedCrossRefGoogle Scholar
  103. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  104. 104.
    Ziegler SF. FOXP3: not just for regulatory T cells anymore. Eur J Immunol. 2007;37(1):21–3. doi: 10.1002/eji.200636929.PubMedCrossRefGoogle Scholar
  105. 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.PubMedCrossRefGoogle Scholar
  106. 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.PubMedCrossRefGoogle Scholar
  107. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  108. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  109. 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.PubMedCrossRefGoogle Scholar
  110. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  111. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  112. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  113. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  114. 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.PubMedCrossRefGoogle Scholar
  115. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  116. 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.PubMedCrossRefGoogle Scholar
  117. 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.PubMedCrossRefGoogle Scholar
  118. 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.PubMedGoogle Scholar
  119. 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.PubMedCrossRefGoogle Scholar
  120. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  121. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  122. 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.PubMedCentralPubMedCrossRefGoogle Scholar
  123. 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.PubMedCrossRefGoogle Scholar
  124. 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.PubMedCrossRefGoogle Scholar
  125. 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.PubMedCrossRefGoogle Scholar
  126. 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.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Changhua Zhuo
    • 1
    • 2
    • 3
  • Ye Xu
    • 1
    • 2
  • Mingang Ying
    • 3
  • Qingguo Li
    • 1
    • 2
  • Liyong Huang
    • 1
    • 2
  • Dawei Li
    • 1
    • 2
  • Sanjun Cai
    • 1
    • 2
  • Bin Li
    • 4
  1. 1.Department of Colorectal SurgeryFudan University Shanghai Cancer CenterShanghaiPeople’s Republic of China
  2. 2.Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiPeople’s Republic of China
  3. 3.Department of Surgical Oncology, Fujian Provincial Cancer HospitalTeaching Hospital of Fujian Medical UniversityFuzhouPeople’s Republic of China
  4. 4.Key Laboratory of Molecular Virology and Immunology, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological SciencesChinese Academy of SciencesShanghaiPeople’s Republic of China

Personalised recommendations