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The Role of Regulatory T Cells in Cancer

  • Ha, Tai-You (Department of Immunology, Chonbuk National University Medical School)
  • Received : 2009.11.11
  • Accepted : 2009.11.11
  • Published : 2009.12.31

Abstract

There has been an explosion of literature focusing on the role of regulatory T (Treg) cells in cancer immunity. It is becoming increasingly clear that Treg cells play an active and significant role in the progression of cancer, and have an important role in suppressing tumor-specific immunity. Thus, there is a clear rationale for developing clinical strategies to diminish their regulatory influences, with the ultimate goal of augmenting antitimor immunity. Therefore, manipulation of Treg cells represent new strategies for cancer treatment. In this Review, I will summarize and review the explosive recent studies demonstrating that Treg cells are increased in patients with malignancies and restoration of antitumor immunity in mice and humans by depletion or reduction of Treg cells. In addition, I will discuss both the prognostic value of Treg cells in tumor progression in tumor-bearing hosts and the rationale for strategies for therapeutic vaccination and immunotherapeutic targeting of Treg cells with drugs and microRNA.

Keywords

References

  1. Block MS, Markovic SN: The tumor/immune interface: clinical evidence of cancer immunosurveillance, immunoediting and immunosubversion. Am J Immunol 5;29-40, 2009 https://doi.org/10.3844/ajisp.2009.29.49
  2. Zitvogel L, Tesniere A, Kroemer G: Cancer despite immunosurveillance: immunoselectionand immunosubversion. Nat Rev Immunol 6;715-727, 2006 https://doi.org/10.1038/nri1936
  3. Dougan M, Dranoff G: Immune therapy for cancer. Ann Rev Immunol 27;83-117, 2009 https://doi.org/10.1146/annurev.immunol.021908.132544
  4. Fujimoto S, Greene MI, Sehon AH: Regulation of the immune response to tumor antigens. II. The nature of immunosuppressor cells in tumor-bearing hosts. J Immunol 116;800-806, 1976
  5. Ha TY, Park HJ, On KK, Lee HK, Lee JH, Lee MY: Potentiation of anti-tumor immunity by modulation of suppressor T cells. II. Regression of tumor by modulation of suppressor T cells. Korean J Immunol 17;101-118, 1995
  6. Gershon RK, Cohen P, Hencin R, Liebhaber SA: Suppressor T cells. J Immunol 108;586-590, 1972
  7. Gershon RK, Kondo K: Infectious immunological tolerance. Immunol 21;903-914, 1971
  8. Durkin HG, Waksman BH: Thymus and tolerance. Is regulation the major function of the thymus? Immunol Rev 182;33-57, 2001 https://doi.org/10.1034/j.1600-065X.2001.1820103.x
  9. Waksman BH: Tolerance, the thymus, and suppressor T cells. Clin Exp Immunol 28;363-374, 1977
  10. 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 mechanisms of self-tolerance causes various autoimmune diseases. J Immunol 155;1151-1164, 1995
  11. Sakaguchi S: Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune response. Ann Rev Immunol 22;531-562, 2004 https://doi.org/10.1146/annurev.immunol.21.120601.141122
  12. Zou W: Regulatory T cells, tumor immunity and immunotherapy. Nat Rev Immunol 6;295-307, 2006 https://doi.org/10.1038/nri1806
  13. Beyer M, Schultze JL: Regulatory T cells in cancer. Blood 108;804-811, 2006 https://doi.org/10.1182/blood-2006-02-002774
  14. Curiel TJ: Tregs and rethinking cancer immunotherapy. J Clin Invest 117;1167-1174, 2007 https://doi.org/10.1172/JCI31202
  15. Yang ZZ, Ansell SM: The role of Treg cells in the cancer immunological response. Am J Immunol 5:17-28, 2009 https://doi.org/10.3844/ajisp.2009.17.28
  16. Shen LS, Wang J, Shen DF, Yuan XL, Dong P, Li MX, Xue J, Zhang FM, Ge HL, Xu D: CD4+CD25+CD127(low/-) regulatory T cells express Foxp3 and suppress effector T cell proliferation and contribute to gastric cancers progression. Clin Immunol 131;109-118, 2009 https://doi.org/10.1016/j.clim.2008.11.010
  17. Ke X, Wang J, Li L, Chen IM, Wang H, Yang XF: Roles of CD4+CD25(high)FOXP3 Tregs in lymphomas and tumors are complex. Front Biosci 13;3986-4001, 2008
  18. Schabowsky RH, Madiredii S, Sharma R, Yolcu ES, Shirwan H: Targeting CD4+CD25+Foxp3+ regulatory T-cells for the augmentation of cancer immunotherapy. Curr Opin Invest Drugs 8;1002-1008, 2007
  19. Jarnicki AG, Conroy H, Brereton C, Donnelly G, Toomey D, Walsh K, Sweeney C, Leavy O, Fletcher J, Lavelle EC, Dunne P, Mills KH: Attenuating regulatory T cell induction by TLR agonists through inhibition of p38 MAPK signaling in dendritic cells enhances their efficacy as vaccine adjuvants and cancer immunotherapeutics. J Immunol 180; 3797-3806, 2008 https://doi.org/10.4049/jimmunol.180.6.3797
  20. Nicholaou T, Ebert LM, Davis ID, McArthur GA, Jackson H, Dimopoulos N, Tan B, Maraskovsky E, Miloradovic L, Hopkins W, Pan L, Venhaus R, Hoffman EW, Chen W, Cebon J: Regulatory T-cell-mediated attenuation of T-cell responses to the NY-ESO-1 ISCOMATRIX vaccine in patients wih advanced malignant melanoma. Clin Cancer REs 15;2166-2173, 2009 https://doi.org/10.1158/1078-0432.CCR-08-2484
  21. Curiel TJ: Regulatory T cells and treatment of cancer. Curr Opin Immunol 20;241-246, 2008 https://doi.org/10.1016/j.coi.2008.04.008
  22. Leon K, Carcia K, Carneiro J, Lage A: How regulatory CD25+CD4+ T cells impinge on tumor immunobiology: The differential response of tumors to therapies. J Immunol 179;5659-5668, 2007 https://doi.org/10.4049/jimmunol.179.9.5659
  23. Tokuno K, Hazama S, Yoshino S, Yshida S, Oka M: Increased prevalence of regulatory T-cells in the peripheral blood of patients with gastrointestinal cancer. Anticancer Res 29;1527-1532, 2009
  24. Carreras J, Lopez-Guillermo A, Roncador G, Vilamor N, Colomo L, Marinez A, Hamoudi R, Howat WJ, Montserrat E, Campo E: High numbers of tumor-infiltrating programmed cell death 1-positive regulatory lymphocytes are associated with improved overall survival in follicular lymphoma. J Clin Oncol 27;1470-1476, 2009 https://doi.org/10.1200/JCO.2008.18.0513
  25. Liu Z, Kim JH, Falo LD Jr, You Z: Tumor regulatory T cells potently abrogate antitimor immunity. J Immunol 182;6160-6167, 2009 https://doi.org/10.4049/jimmunol.0802664
  26. Salama P, Phillips M, Grieu F, Moris M, Zepts N, Joseph D, Platell C, Iacopetta B: Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol 27;186-192, 2009 https://doi.org/10.1200/JCO.2008.18.7229
  27. Wang RF: Regulatory T cells and innate immune regulation in tumor immunity. Springer Semin Imunopathol 28;17-23, 2006 https://doi.org/10.1007/s00281-006-0022-7
  28. Fietta AM, Morosini M, Passadore I, Cascina A, Draghi P, Dore R, Rossi S, Pozzi E, Meloni F: Systemic inflammatory response and downmodulation of peripheral CD25+ Foxp3+ T-regulatory cells in patients undergoing raidofrequency thermal ablation for lung cancer. Human Immunol 70;477-486, 2009 https://doi.org/10.1016/j.humimm.2009.03.012
  29. Morse MA, Hobeika AC, Osada T, Serra D, Niedzwiecki D, Lyerly HK, Clay TM: Depletion of human regulatory T cells specifically enhances antigen-specific immune responses to cancer vaccines. Blood 112; 610-618, 2008 https://doi.org/10.1182/blood-2008-01-135319
  30. Ruter J, Barnett BG, Kryczek I, Brumlik MJ, Daniel BJ, Coukos G, Zou W, Curiel TJ: Altering regulatory T cell function in cancer immunotherapy: a novel means to boost the efficacy of cancer vaccines. Front Biosci 14; 1761-1770, 2009
  31. Mailloux AW, Young MR: NK-dependent increases in CCL22 secretion selectively recruits regulatory T cells to the tumor microenvironment. J Immunol 182;2753-2765, 2009 https://doi.org/10.4049/jimmunol.0801124
  32. Liyanage UK, Goedegebuure PS, Moore TT, Viehl CT, Moo-Young TA, Larson JW, Frey DM, Ehlers JP, Eberlein TJ, Linehan DC: Increase prevalence of regulatory T cells (Treg) is induced by pancreas adenocarcinoma. J Immunother 29;416-424, 2006 https://doi.org/10.1097/01.cji.0000205644.43735.4e
  33. Lizee G, Radvanyi LG, Overwijk WW, Hwu P: Improving antitumor immune responses by circumventing immunoregulatory cells and mechanisms. Clin Cancer Res 12; 4794-4803, 2006 https://doi.org/10.1158/1078-0432.CCR-06-0944
  34. Lin YC, Chang LY, Huang CT, Peng HM, Dutta A, Chen TC, Yeh CT, Lin CY: Effector/memory but not naive regulatory T cells are responsible for the loss of concomitant tumor immunity. J Immunol 182;6095-6104, 2009 https://doi.org/10.4049/jimmunol.0803829
  35. van der Viliet HJ, Koon HB, Atkins MB, Balk SP, Exley MA: Exploiting regulatory T-cell populations for the imunotherapy of cancer. J Immunother 30;591-595, 2007 https://doi.org/10.1097/CJI.0b013e31805ca058
  36. Liyanage UK, Moore TT, Joo HG, Tanaka Y, Herrmann V, Doherty G, Drebin JA, Strasberg SM, Eberlein TJ, Goedegebuure PS, Linehan DC: Prevalence of regulatory T cells is increased in peripheral blood and tumor micro-environment of patients with pancreas or breast adenocarcinoma. J Immunol 169:2756-2761, 2002 https://doi.org/10.4049/jimmunol.169.5.2756
  37. Ormandy LA, Hillemann T, Wedemeyer H, Manns MP, Greten TF, Korangy F: Increased populations of regulatory T cells in peripheral blood of patients with hepatocellular carcinoma. Cancer Res 65;2457-2464, 2005 https://doi.org/10.1158/0008-5472.CAN-04-3232
  38. Matkowski R, Gisterek I, Halon A, Lacko A, Szewczyk K, Staszek U, Pudelko M, Szynglarewicz B, Szelachowska J, Zolnierek A, Kornafel J: The prognostic role of tumor-infiltrating CD4 and CD8 T lymphocytes in breast cancer. Anticancer Res 29;2445-2451, 2009
  39. Schreiber TH: The use of FoxP3 as a biomarker and prognostic factor for malignant human tumors. Cancer Epidemiol Biromarker Prev 16;1931-1934, 2007 https://doi.org/10.1158/1055-9965.EPI-07-0396
  40. Siddiqui SA, Frigola X, Bonne-Annee S, Mercader M, Kuntz SM, Krambeck AE, Sengupta S, Dong H, Cheville JC, Lohse CM, Krco CJ, Webster WS, Leibovich BC, Blute ML, Knutson KL, Kwon ED: Tumor-infiltrating Foxp3-CD4+CD25+ T cells predict poor survival in renal cell carcinoma. Clin Cancer Res 13;2075-2081, 2007 https://doi.org/10.1158/1078-0432.CCR-06-2139
  41. Heimberger AB, Abou-Ghazal M, Reina-Ortiz C, Yang DS, Sun W, Qiao W, Hiraoka N, Fuller GN: Incidence and prognostic impact of FoxP3+ regulatory T cells in human gliomas. Clin Cancer Res 14;5166-5172, 2008 https://doi.org/10.1158/1078-0432.CCR-08-0320
  42. Nishikawa H, Jager E, Ritter G, Old LJ, Gnjatic S: $CD4^{+}CD25^{+}$ regulatory Tcells control the induction of antigen-specific $CD4^{+}$ helper T cell responses in cancer patients. Blood 106;1008-1011, 2005 https://doi.org/10.1182/blood-2005-02-0607
  43. Mahnke K, Schonfeld K, Fondel S, Ring S, Karakhanova S, Wiedemeyer K, Bedke T, Johnson TS, Storn V, Schallenberg S, Enk AH: Depletion of CD4+CD25+ human regulatory T cells in vivo: kinetics of Treg depletion and alterations in immune functions in vivo and in vitro. Int J Cancer 120;2723-2733, 2007 https://doi.org/10.1002/ijc.22617
  44. Juang CM, Hung CF, Yeh JY, Horng HC, Twu NF, Cheng MH, Wen KC, Yuan CC, Chao KC, Wu TC, Yen MS: Regulatory T cells: Potential target in anticancer immunotherapy. Taiwan J Obstet Gynecol 46;215-221, 2007 https://doi.org/10.1016/S1028-4559(08)60023-6
  45. Shevach EM: Mechanisms of Toxp3+ T regulatory cell-medicated suppression. Immunity 30;636-645, 2009 https://doi.org/10.1016/j.immuni.2009.04.010
  46. Ha TY: The role of suppressor T cells in mycobacterial infection. Korean Lepr Bull 41;3-25, 2008
  47. Ha TY: Regulatory T cell therapy for autoimmune disease. Immune Netw 8;107-123, 2008 https://doi.org/10.4110/in.2008.8.4.107
  48. Ha TY: The role of suppressor T cells in bacterial infections. KAST Rev Modern Sci & Technol 4;105-120, 2008
  49. Shevach EM: Certified professionals: CD4+ CD25+ suppressor T cells. J Exp Med 193:F41-46, 2001 https://doi.org/10.1084/jem.193.11.F41
  50. Mudd PA, Teague BN, Farris AD: Regulatory T cells and systemic lupus erythematosus. Scand J Immunol 64;211-218, 2006 https://doi.org/10.1111/j.1365-3083.2006.01808.x
  51. Ha TY, Waksman BH: Role of the thymus in tolerance.X. "Suppressor" activity of antigen-stimulated rat thymocytes transferred to normal recipients. J Immunol 110; 1290-1299, 1973
  52. Ha TY, Waksman BH, Treffers HP: Thymic suppressor cell. I. Separation of subpopulation with suppressor activity. J Exp Med 139;13-23, 1974 https://doi.org/10.1084/jem.139.1.13
  53. Ha TY, Waksman BH, Treffers HP: The thymic suppressor cell. II. Metabolic requirement of suppressor activity. Immunol Commun 3;351-359, 1974 https://doi.org/10.3109/08820137409061115
  54. Riley JL, June CH, Blazar BR: Human T regulatory cell therapy: take a billion or so and call me in the morning. Immunity 30;656-665, 2009 https://doi.org/10.1016/j.immuni.2009.04.006
  55. Mabarrack NH, Turner NL, Mayrhofer G: Recent thymic origin, differentiation, and turnover of regulatory T cells. J Leukoc Biol 84;1287-1297, 2008 https://doi.org/10.1189/jlb.0308201
  56. Ziegler SF: FOXP3: of mice and men. Ann Rev Immunol 24;209-226, 2006 https://doi.org/10.1146/annurev.immunol.24.021605.090547
  57. Miyara M, Yoshioka Y, Kitoh A, Shima T, Wing K, Niwa A, Parizot C, Taflin C, Heike T, Valeyre D, Mathian A, Nakahata T, Yamaguchi T, Nomura T, Ono M, Amoura Z, Gorochov G, Sakaguchi S: Functional delineation and differentiation dynamics of human CD4+ T cells expressing the Foxp3 transcription factor. Immuity 30;899-911, 2009
  58. Qin FX: Dynamic behavior and function of Foxp3+ regulatory T cells in tumor bearing host. Cell Mol Immunol 6;3-13, 2009 https://doi.org/10.1038/cmi.2009.2
  59. Huen J, Polansky JK, Hamann A: Epigenetic control of FOXP3 expression: the key to a stable regulatory T-cell lineage? Nat Rev Immunol 9;83-89, 2009 https://doi.org/10.1038/nri2474
  60. Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY: Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 22;329-341, 2005 https://doi.org/10.1016/j.immuni.2005.01.016
  61. Walker MR, Kasprowicz DJ, Gersuk VH, Benard A, Van Landeghen M, Buckner JH, Ziegler SF: Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+CD25-T cells. J Clin Invest 112;1437-1443, 2003 https://doi.org/10.1172/JCI19441
  62. Hubert P, Jacobs, Caberg JH, Boniver J, Delvenne P: The cross-talk between dendritic and regulatory T cells: good or evil? J Leukoc Biol 82;781-794, 2007 https://doi.org/10.1189/jlb.1106694
  63. Toda A, Piccirillo CA: Development and function of naturally occurring CD4+CD25+ regulatory T cells. J Leukoc Biol 80;458-470, 2006 https://doi.org/10.1189/jlb.0206095
  64. Wang HY, Wang RF: Regulatory T cells and cancer. Curr Opin Immunol 19;217-223, 2007 https://doi.org/10.1016/j.coi.2007.02.004
  65. Han Y, Guo Q, Zhang M, Chen Z, Cao X: CD69+ CD4+ CD25- T cells, a new subset of regulatory T cells, suppress T cell proliferation through membrane-bound TGF-beta 1. J Immunol 182;111-120, 2009 https://doi.org/10.4049/jimmunol.182.1.111
  66. Maggi E, Cosmi L, Liotta F, Romagnani P, Romagnani S, Annunziato F: Thymic regulatory T cells. Autoimmun Rev 4;579-586, 2005 https://doi.org/10.1016/j.autrev.2005.04.010
  67. Generali D, Bates G, Berruti A, Brizzi MP, Camp L, Bonardi S, Bersiga A, Allevi G, Milani M, Aguggini S, Dogliotti L, Banham AH, Harris AL, Bottini A, Fox SB: Immunomodulation of FOXP3+ regulatory T cells by the aromatase inhibitor letrozole in breast cancer. Clin Cancer Res 15;1046-1051, 2009 https://doi.org/10.1158/1078-0432.CCR-08-1507
  68. Powell DJ Jr, Parker LL, Rosenberg SA: Large-scale depletion of CD25+ regulatory T cells from patient leukapheresis samples. J Immunother 28;403-411, 2005 https://doi.org/10.1097/01.cji.0000170363.22585.5a
  69. Beissert S, Schwarz A, Schwarz T: Regulatory T cells. J Invest Dermatol 126;15-24, 2006 https://doi.org/10.1038/sj.jid.5700004
  70. Brahmachari S, Pahan K: Suppression of regulatory T cells by? IL-12p40 homodimer via nitric oxide. J Immunol 183;2045-2058, 2009 https://doi.org/10.4049/jimmunol.0800276
  71. Wan YY, Flavell RA: 'Yin-Yang' functions of transforming growth factor-beta and T regulatory cells in immune regulation. Immunol Rev 220;199-213, 2007 https://doi.org/10.1111/j.1600-065X.2007.00565.x
  72. Curotto de Lafaille MA, Lafaille JJ: Natural and adaptive Foxp3+ regulatory T cells: More of the same or a division of labor? Immunity 30;626-635, 2009 https://doi.org/10.1016/j.immuni.2009.05.002
  73. Zhou X, Bailley-Bucktrout S, Jeker LT, Bluestone JA: Plasticity of CD4+Foxp3+ T cells. Curr Opin Immunol 21;281-285, 2009 https://doi.org/10.1016/j.coi.2009.05.007
  74. Valzasina B, Piconese S, Guiducci C, Conombo MP: Tumor-induced expansion of regulatory? T cells by conversion of CD4+CD25-lymphocytes is thymus and proliferation independent. Cancer Res 66;4488-4895, 2006 https://doi.org/10.1158/0008-5472.CAN-05-4217
  75. Liu VC, Wong LY, Jang T, Shah AH, Park I, Yang X, Zhang Q, Lonning S, Teicher BA, Lee C: Tumor evasion of the immune system by converting CD4+CD25- T cells into CD4+CD25+ T regulatory cells: role of tumor-derived TGF-beta. J Immunol 178;2883-2892, 2007 https://doi.org/10.4049/jimmunol.178.5.2883
  76. Viel CT, Moore TT, Liyanage UK, Frey DM, Ehlers JP, Eberlein TJ, Goedegebuure PS, Linehan DC: Depletion of CD4+CD25+ regulatory T cells promotes a tumor-specific immune response in pancreas cancer-bearing mice. Ann Surg Oncol 13;1252-1258, 2006 https://doi.org/10.1245/s10434-006-9015-y
  77. Antony PA, Piccirillo CA, Akpinarli A, Finkelstein SE, Speiss PJ, Surman DR, Palmer DC, Chan CC, Klebanoff CA, Overwijk WW, Rsoenberg SA, Restifo NP: CD8+ T cell immunity against a tumor/self-antigen is augmented by CD4+ T helper cells and hindered by naturally occurring T regulatory cells. J Immunol 174;2591-2601, 2005 https://doi.org/10.4049/jimmunol.174.5.2591
  78. Linehan DC, Goedegebuure PS: CD25+CD4+ regulatory T-cells in cancer. Immunol Res 32;155-168, 2005 https://doi.org/10.1385/IR:32:1-3:155
  79. Hiur T, Kagamu H, Miur S, Ishida A, Tanaka H, Tanaka J, Gejyo F, Yshizawa H: Both regulatory T cells and antitumor effector T cells are primed in the same draining lymph nodes during tumor progression. J Immunol 175; 5058-5066, 2005 https://doi.org/10.4049/jimmunol.175.8.5058
  80. Hontsu S, Yoneyama H, Ueha S, Terashima Y, Kitabatake M, Nakan A, It T, Kimura H, Matsushima K: Visualization of naturally occurring Foxp3+ regulatory T cells in normal and tumor-bearing mice. Int Immunopharmacol 4;1785-1793, 2004 https://doi.org/10.1016/j.intimp.2004.07.026
  81. Tien AH, Xu L, Helgason CD: Altered immunity accompanies disease progression in a mouse model of prostate dysplasia. Cancer Res 65;2947-2955, 2005 https://doi.org/10.1158/0008-5472.CAN-04-3271
  82. Liu JY, Zhang XS, Ding Y, Peng RQ, Cheng X, Zhang NH, Xia JC, Zeng YX: The changes of $CD4^{+}CD25^{+}/CD4^{+}$proportion in spleen of tumor-bearing BALB/c mice. J Transl Med 3;5, 2005 https://doi.org/10.1186/1479-5876-3-5
  83. Golgher D, Jones E, Powrie F, Elliott T, Gallimore A: Depletion of CD25+regulatory cells uncovers immune responses to shared murine tumor rejection antigens. Eur J Immunol 32:3267-3275, 2002 https://doi.org/10.1002/1521-4141(200211)32:11<3267::AID-IMMU3267>3.0.CO;2-1
  84. Ghiringhelli F, Lamonier N, Schmitt E, Parcellier A, Cathelin D, Garrido C, Chauffert B, Solary E, Bonnotte B, Martin F: CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative. Eur J Immunol 34;336-344, 2004 https://doi.org/10.1002/eji.200324181
  85. El Andaloussi A, Han Y, Lesniak MS: Prolongation of survival following depletion of CD4+CD25+ regulatory T cells in mice with experimental brain tumors. J Neurosurg 105;430-437, 2006 https://doi.org/10.3171/jns.2006.105.3.430
  86. Sutmuller RP, van Duivenvoorde LM, van Elsas A, Schumacher TN, Wildenberg ME, Allison JP, Toes RE, Offringa R, Melief CJ: Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25(+) regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses. J Exp Med 194:823-832, 2001 https://doi.org/10.1084/jem.194.6.823
  87. Sharma S, Yang SC, Zhu L, Reckamp K, Gardner B, Baratelli F, Huang M, Batra RK, Dubinett SM: Tumor cyclooxygenase-2/prostaglandin E2-dependent promotion of FOXP3 expression and CD4+CD25+ T regulatory cell activities in lung cancer. Cancer Res 65;5211-5220, 2005 https://doi.org/10.1158/0008-5472.CAN-05-0141
  88. Turk MJ, Guevara-Patino JA, Rizzuto GA, Engelhorn ME, Sakaguchi S, Houghton AN: Concomitant tumor immunity to a poorly immunogenic melanoma is prevented by regulatory T cells. J Exp Med 200;771-782, 2004 https://doi.org/10.1084/jem.20041130
  89. Lutsiak ME, Tagaya Y, Adams AJ, Schlom J, Sabzevari H: Tumor-induced impairment of TCR signaling results in compromised functionality of tumor-infiltrating regulatory T cells. J Immunol 180;5871-5881, 2008 https://doi.org/10.4049/jimmunol.180.9.5871
  90. Mizukami Y, Kono K, Kawaguchi Y, Akaike H, Kamimur K, Sugai H, Fujii H: CCL17 and CCL22 chemokines within tumor environment are related to accumulation of Toxp3+ regulatory T cells in gastric cancer. Int J Cancer 122;2286-2293, 2008 https://doi.org/10.1002/ijc.23392
  91. Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, Zhu Y, Wei S, Kryczek I, Daniel B, Gordon A, Myers L, Lackner A, Disis ML, Knutson KL, Chen L, Zou W: Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10;942-949, 2004 https://doi.org/10.1038/nm1093
  92. Grauer OM, Nierkens S, Bennink E, Toonen LW, Boon L, Wesseling P, Sutmuller RP, Adema GJ: CD4+Foxp3+ regulatory T cells gradually accumulate in glioma during tumor growth and efficiently suppress antiglioma immue responses in vivo. Int J Cancer 121;95-105, 2007 https://doi.org/10.1002/ijc.22607
  93. 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 163;5211-5218, 1999
  94. Tanaka H, Tanaka J, Kjaegaard J, Shu S: Depletion of CD4+CD25+ regulatory cells augments the generation of specific immune T cells in tumor-draining lymph nodes. J Immunother 25;207-217, 2002 https://doi.org/10.1097/00002371-200205000-00003
  95. Prasad SJ, Farrand KJ, Matthews SA, Chang JH, McHugh RS, Ronchese F: Dendritic cells loaded with stressed tumor cells elicit long-lasting protective tumor immunity in mice depleted of CD4+CD25+regulatory T cells. J Immunol 174:90-98, 2005 https://doi.org/10.4049/jimmunol.174.1.90
  96. Van Meirvenne S, Dullaers M, Heirman C, Straetman L, Michiels A, Thielemans K: In vivo depletion of CD4+CD25+regulatory T cells enhances the antigen-specific primary and memory CTL response elicited by mature mRNA-electroporated dendritic cells. Mol Ther 12:922-932, 2005 https://doi.org/10.1016/j.ymthe.2005.02.029
  97. Onizuka S, Tawara I, Shimizu J, Sakaguchi S, Fujita T, Nakayama E: Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor $\alpha$) monoclonal antibody. Cancer Res 59;3128-3133, 1999
  98. Fu T, Shen Y, Fujimoto S: Tumor-specific CD4(+) suppressor T-cell clone capable of inhibiting rejection of syngeneic sarcoma in A/J mice. Int J Cancer 87:680-687, 2000 https://doi.org/10.1002/1097-0215(20000901)87:5<680::AID-IJC10>3.0.CO;2-P
  99. Jones E, Dahm-Vicker M, Simon AK, Green A, Powrie F, Cerundolo V, Gallimore A: Deletion of CD25+ regulatory cells results in suppression of melanoma growth and induction of autoreactivity in mice. Cancer Immun 2;1, 2002
  100. Casares N, Arribillaga L, Sarobe P, Dotor J, Lopez-Diaz de Cerio A, Melero I, Prieto J, Borras-Cuesta F, Lasarte JI: CD4+/CD25+regulatory cells inhibit activation of tumor-primed CD4+Tcells with IFN-$\gamma$-dependent antiangiogenic activity, as well as long-lasting tumor immunity elicited by peptide vaccination. J Immunol 171;5931-5939, 2003 https://doi.org/10.4049/jimmunol.171.11.5931
  101. Yu P, Lee Y, Liu W, Krausz T, Chong A, Schreiber H, Fu YX: Intratumor depletion of CD4+ cells unmasks tumor immunogenicity leading to the rejection of late-stage tumors. J Exp Med 201;779-791, 2005 https://doi.org/10.1084/jem.20041684
  102. Quezada SA, Peggs KS, Simpson TR, Shen Y, Littman DR, Allison JP: Limited tumor infiltration by activated T effector cells restricts the therapeutic activity of regulatory T cell depletion against established melanoma. J Exp Med 205;2125-2138, 2008 https://doi.org/10.1084/jem.20080099
  103. Wrzesinski C, Paulos CM, Gattinoni L, Palmer DC, Kaiser A, Yu Z, Rosenberg SA, Restifo NP: Hematopoietic stem cells promote the expansion and function of adoptively transferred antitumor CD8 T cells. J Clin Invest 117;492-501, 2007 https://doi.org/10.1172/JCI30414
  104. Heier I, Mofgaard PO, Brandtzaeg P, Jahnsen FL, Karisson M: Depletion of CD4+CD25+ regulatory T cells inhibits local tumour growth in a mouse model of B cell lymphoma. Clin Exp Immunol 152;381-387, 2008 https://doi.org/10.1111/j.1365-2249.2008.03642.x
  105. Lee CH, Chiang YH, Chang SE, Chong CL, Cheng BM, Roffler SR: Tumor-localized ligation of CD3 and CD28 with systemic regulatory T-cell depletion induces potent innate and adaptive antitumor response. Clin Cancer Res 15; 2756-2766, 2009 https://doi.org/10.1158/1078-0432.CCR-08-2311
  106. Chen YL, Fang JH, Lai MD, Shan YS: Depletion of CD4(+)CD25(+) regulatory T cells can promote local immunity to suppress tumor growth in benzo[a]pyrene-induced forestomach carcinoma. World J Gastroenterol 14;5797-5809, 2008 https://doi.org/10.3748/wjg.14.5797
  107. Tan MC, Goedegebuure PS, Belt BA, Flaherty B, Sankpal N, Gillanders WE, Eberlein TJ, Hsieh CS, Linehan DC: Distribution of CCR5-dependent homing of regulatory T cells inhibits tumor growth in a murine model of pancreatic cancer. J Immunol 182;1746-1755, 2009 https://doi.org/10.4049/jimmunol.182.3.1746
  108. Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, Nomura T, Sakaguchi S: CTLA-4 control over Foxp3+ regulatory T cell function. Science 322;271-275, 2008 https://doi.org/10.1126/science.1160062
  109. Woo EY, Chu CS, Goletz TJ, Schlienger K, Yeh H, Coukos G, Rubin SC, Kaiser LR, June CH: regulatory CD4(+) CD25(+) T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. Cancer Res 61;4766-4772, 2001
  110. Woo EY, Yeh H, Chu CS, Schlienger K, Carrol RG, Riley JL, Kaiser LR, June CH: Cutting edge: Regulatory T cells from lung cancer patients directly inhibit autologous T cell proliferation. J Immunol 168;4272-4276, 2002 https://doi.org/10.4049/jimmunol.168.9.4272
  111. Orentas RJ, Kohler ME, Johnson BD: Suppression of anti-cancer immunity by regulatory T cells: back to the future. Seminar Cancer Biol 16;137-149, 2006 https://doi.org/10.1016/j.semcancer.2005.11.007
  112. Danesse S, Rutella S: The Janus face of CD4+CD25+ regulatory T cells in cancer and autoimmunity. Curr Med Chem 14;649-666, 2007 https://doi.org/10.2174/092986707780059599
  113. Barnett BG, Ruter J, Kryczek I, Brumlik MJ, Cheng PJ, Daniel BJ, Coukos G, Zou W, Curiel TJ: Regulatory T cells: a new frontier in cancer immunotherapy. Adv Exp Med Biol 622;255-260, 2008
  114. Sasada T, Kimura M, Yoshida Y, Kanai M, Takabayashi A: CD4+CD25+ regulatory Tcells in patients with gastrointestinal malignancies: possible involvement of regulatory T cells in disease progression. Cancer 98;1089-1099, 2003 https://doi.org/10.1002/cncr.11618
  115. Kawaida H, Kono K, Takahashi A, Sugai H, Mimura K, Miyagawa N, Omata H, Ooi A, Fujii H; Distribution of CD4+CD25high regulatory T-cells in tumor-draining lymph nodes in patients with gastric cancer. J Surg Res 124;151-157, 2005 https://doi.org/10.1016/j.jss.2004.10.004
  116. Kono K, Kawaida H, Takahashi A, Sugai H, Mimura K, Myyagawa N, Omata H, Fujii H: CD4(+) $CD25^{high}$ regulatory T cells increase with tumor stage in patients with gastric and esophageal cancers. Cancer Immunol Immunother 55;1064-1071, 2006 https://doi.org/10.1007/s00262-005-0092-8
  117. Ichihara F, Kono K, Takahashi A, Kawaida H, Sugai H, Fujii H: Increased populations of regulatory T cells in peripheral blood and tumor-infiltrating lymphocytes in patients with gastric and esophageal cancers. Clin Cancer Res 9;4404-4408, 2003
  118. Xu H, Mao Y, Dai Y, Wang Q, Zhang X: CD4+CD25+ regulatory T cells in patients with advanced gastrointestinal cancer treated with chemotherapy. Onkologie 32;246-252, 2009
  119. Gobert M, Treilleux I, Bendriss-Vermare N, Bachelot T, Goddard-Leon S, Arfi V, Bitoa C, Doffin AC, Durand I, Olive D, Perez S, Pasqual N, Faure C, Ray-Coquard I, Puisieux A, Caux C, Blay JY, Menetrier-Caux C: Regulatory T cells recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome. Cancer Res 69;2000-2009, 2009 https://doi.org/10.1158/0008-5472.CAN-08-2360
  120. Qin XJ, Shi HZ, Deng JM, Liang QL, Jiang J, Ye ZJ: CCL22 recruits CD4-positive CD25-positive regulatory T cells into malignant pleural effusion. Clin Cancer Res 15;2231-2237, 2009 https://doi.org/10.1158/1078-0432.CCR-08-2641
  121. Wieczorek G, Asemissen A, Model F, Turbachova I, Floess S, Liebenberg V, Baron U, Stauch D, Kotsch K, Pratschke J, Hamann A, Loddenkemper C, Stein H, Volk HD, Hoffmuller U, Grutzkau A, Mustea A, Huehn J, Scheibenbogen C, Olek S: Quantitative DNA methylation analysis of FOXP3 as a new method for counting regulatory T cells in peripheral blood and solid tissue. Cancer Res 69;599-608, 2009 https://doi.org/10.1158/0008-5472.CAN-08-2361
  122. Schaefer C, Kim GG, Albers A, Hoermann K, Myers EN, Whiteside TL: Characteristics of CD4+CD25+ regulatory T cells in the peripheral circulation of patients with head and neck cancer. Br J Cancer 92;913-920, 2005 https://doi.org/10.1038/sj.bjc.6602407
  123. Strauss L, Bergmann C, Gooding W, Johnson JT, Whiteside TL: The frequency and suppressor function of CD4+CD25highFoxp3+ T cells in the circulation of patients with squamous cell carcinoma of the head and neck. Clin Cancer Res 13;6301-6311, 2007 https://doi.org/10.1158/1078-0432.CCR-07-1403
  124. Gao Q, Qiu SJ, Fan J, Zhou J, Wang XY, Xiao YS, Xu Y, Li YW, Tang ZY: Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol 25;2586-2593, 2007 https://doi.org/10.1200/JCO.2006.09.4565
  125. Kobayashi N, Hiraoka N, Yamagami W, Ojima H, Kanai Y, Kosuge T, Nakajima A, Hirohashi S: FOXP3+ regulatory T cells affect the development and progression of hepatocarinogenesis. Clin Cancer Res 13:902-911, 2007 https://doi.org/10.1158/1078-0432.CCR-06-2363
  126. Gray CP, Arosio P, Hersey P: Association of increased levels of heavy-chain ferritin with increased CD4+$CD25^{+}$regulatory T-cell levels in patients with melanoma. Clin Cancer Res 9;2551-2559, 2003
  127. Viguier M, Lemaitre F, Verola O, Cho MS, Gorochov G, Dubertret L, Bachelez H, Kourilsky P, Ferradini L: 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 173;1444-1453, 2004 https://doi.org/10.4049/jimmunol.173.2.1444
  128. Mao C, Wang S, Jiang Q, Tong J, Ma J, Yang M, Xu X, Qiu G, Shao Q, Li L, Xu H: Increased CD4+CD25+FOXP3+ regulatory T cells in cancer patients from conversion of CD4+CD25-T cells through tumor-derived factors. Onkologie 31;243-248, 2008 https://doi.org/10.1159/000121360
  129. Powell DP Jr, Felipe-Silva A, Merino MJ, Ahmadzadeh M, Allen T, Levy C, Whie DE, Mavroukakis S, Kreitman RJ, Rosenberg SA, Pastan I: Administration of a CD25-directed immunotoxin, LMB-2, to patients with metastatic melanoma induces a selective partial reduction in regulatory T cells in vivo. J Immunol 179;4919-4928, 2007 https://doi.org/10.4049/jimmunol.179.7.4919
  130. Javia LR, Rosenberg SA: $CD4^{+}$CD25+suppressor lymphocytes in the circulation of patients immunized against melanoma antigens. J Immunother 26;85-93, 2003 https://doi.org/10.1097/00002371-200301000-00009
  131. McCarter MD, Baumgartner J, Escobar GA, Richter D, Lewis K, Robinson W, Wilson C, Palmer BE, Gonzalez R: Immunosuppressive dendritic and regulatory T cells are upregulated in melanoma patients. Ann Surg Oncol 14; 2854-2860, 2007 https://doi.org/10.1245/s10434-007-9488-3
  132. Vence L, Palucka AK, Fay JW, Ito T, Liu YJ, Bancherau J, Ueno H: Circulating tumor antigen-specific regulatory T cells in patients with metastatic melanoma. Proc Natl Acad Sci USA 104;20884-20889, 2007 https://doi.org/10.1073/pnas.0710557105
  133. Pallandre JR, Brillard E, Crehange G, Radlolvie A, Remy-Martin JP, Saas P, Rohrlich PS, Pivot X, Ling X, Tiberghien P, Borg C: Role of STAT3 in CD4+CD25+FOXP3+ regulatory lymphocyte generation: implications in graft-versus-host disease and antitumor immunity. J Immunol 179; 7593-7604, 2007. https://doi.org/10.4049/jimmunol.179.11.7593
  134. Wang W, Edington HD, Rao UN, Jukic DM, Radfar A, Wang H, Kirkwood JM: Effects of high-dose IFN$\alpha$2b on regional lymph node metastases of human melanoma: Modulation of STAT5, FOXP3, and IL-17. Clin Cancer Res 14;8314-8320, 2008 https://doi.org/10.1158/1078-0432.CCR-08-0705
  135. Ahmadzadeh M, Rosenberg SA: IL-2 administration increases CD4+CD25(hi) Foxp3+regulatory T cells in cancer patients. Blood 107;2409-2414, 2006 https://doi.org/10.1182/blood-2005-06-2399
  136. Hiraoka N, Onozato K, Kosuge T, Hirohashi S: Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin Cancer Res 12;5423-5434, 2006 https://doi.org/10.1158/1078-0432.CCR-06-0369
  137. Miller AM, Lundberg K, Ozenci V, Banham AH, Hellstrom M, Egevad L, Pisa P: CD4+$CD25^{high}$ T cells are enriched in the tumor and peripheral blood of prostate cancer patients. J Immunol 177;7398-7405, 2006 https://doi.org/10.4049/jimmunol.177.10.7398
  138. Rozkova D, Tiserova H, Fucikova J, Last'ovicka J, Podrazil M, Ulcova H, Budinsky V, Prausova J, Linke Z, Minarik I, Sediva A, Spisek R, Bartunkova J: FOCUS on FOCIS: combined chemo-immunotherapy for the treatment of hormone-refractory metastatic prostate cancer. Clin Immunol 131;1-10, 2009 https://doi.org/10.1016/j.clim.2009.01.001
  139. 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 15;1052-1058, 2009 https://doi.org/10.1158/1078-0432.CCR-08-1296
  140. Li, X, Ye DF, Xie X, Chen HZ, Lu WG: Proportion of CD4CD25 regulatory T cell is increased in the patients with ovarian carcinoma. Cancer Invest 23;399-403, 2005
  141. Leffers N, Gooden MJM, de Jong RA, Hoogeboom BN, ten Hoor KA, Hollema H, Boezen HM, van der Zee AGJ, Daemen T, Nijman HW: Prognostic significance of tumor-infiltrating T-lymphocytes in primary and metastatic lesion of advanced stage ovarian cancer. Cancer Immunol Immunother 58;449-459, 2009 https://doi.org/10.1007/s00262-008-0583-5
  142. Fattorossi A, Battaglia A, Ferrandina G, Coronetta F, Legge F, Salutari V, Scambia G: Neoadjuvant therapy changes the lymphocyte composition of tumor-draining lymph nodes in cervical carcinoma. Cancer 100;1418-1428, 2004 https://doi.org/10.1002/cncr.20130
  143. Fattorossi A, Battaglia A, Ferrandina G, Buzzonetti A, Legge F, Salutari V, Scambla G: Lymphocyte compostion of tumor draining lymphnodes from cervical and endometrial cancer patients. Gynecol Oncol 92;106-115, 2004 https://doi.org/10.1016/j.ygyno.2003.09.020
  144. Wolf AM, Wof D, Steurer M, Gastl G, Gunsilius E, Grubeck-Loebenstein B: Increase of regulatory T cells in the peripheral blood of cancer patients. Clin Cancer Res 9;606-612, 2003
  145. Bates GJ, Fox SB, Han C, Leek RD, Garcia JF, Harris A, Banham AH: Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and hose at risk of late relapse. J Clin Oncol 24;5373-5380, 2006 https://doi.org/10.1200/JCO.2006.05.9584
  146. Ohara M, Yamaguchi Y, Matsuura K, Murakami S, Arihiro K, Okada M: Possible involvement of regulatory T cells in tumor onset and progression in primary breast cancer. Cancer Immunol Iimmunother 58;441-447, 2009 https://doi.org/10.1007/s00262-008-0570-x
  147. Hueman MT, Stojadinovic A, Storrer CE, Foley RJ, Gurney JM, Shriver CD, Ponniah S, Peoples GE: Levels of circulating regulatory CD4+CD25+ T cells are decreased in breast cancer patients after vaccination with a HER2/neu peptide (E75) and GM-CSF vaccine. Breast Cancer Res Treat 98; 17-29, 2006 https://doi.org/10.1007/s10549-005-9108-5
  148. Merio A, Casalini P, Carcangiu ML, Malventano C, Triulzi T, Menard S, Tagliabue E, Balsari A: FOXP3 expression and overall survival in breast cancer. J Clin Oncol 27; 1746-1752, 2009 https://doi.org/10.1200/JCO.2008.17.9036
  149. Lehe C, Ghebeh H, Al-Sulaiman A, Al Qudaihi G, Al-Hussein K, Almohareb F, Chaudhri N, Alsharif F, Al-Zahrani H, Tbakhi A, Aljurf M, Dermime S: The Wilms' tumor antigen is a novel target for human CD4+ regulatory T cells: implications for immunotherapy. Cancer Res 68; 6350-6359, 2008 https://doi.org/10.1158/0008-5472.CAN-08-0050
  150. Beyer M, Kochaneck M, Giese T, Endle E, Weihrauch MR, Knolle PA, Classen S, Schultze JL: In vivo peripheral expansion of naive CD4+CD25highFoxp3+ regulatory T cells in patients with multiple myeloma. Blood 107;3940-3949, 2006 https://doi.org/10.1182/blood-2005-09-3671
  151. Prabhala RH, Nerj P, Bae JE, Tassone P, Shammas MA, Allam CK, Daley JF, Chauhan D, Blanchard E, Thatte HS, Anderson KC, Munshi NC: Dysfuntional T regulatory cells in multiple myeloma. Blood 107;301-304, 2006 https://doi.org/10.1182/blood-2005-08-3101
  152. Karube K, Ohshima K, Tsuchiya T, Yamaguchi T, Kawano R, Suzumiya J, Utsunomiya A, Harada M, Kikuchi M: Expression of FoxP3, a key molecule in CD4CD25 regulatory T cells, in adult T-cell leukaemia/lymphoma cells. Br J Haematol 126;81-84, 2004 https://doi.org/10.1111/j.1365-2141.2004.04999.x
  153. Yano H, Ishida T, Inagaki A, Ishii T, Kusumoto S, Komatsu H, Iida S, Utsunomiya A, Ueda R: Regulatory T-cell function of adult T-cell leukemia/lymphoma cells. Int J Cancer 120;2052-2057, 2007 https://doi.org/10.1002/ijc.22536
  154. Motta M, Rassenti L, Shelvin BJ, Lerner S, Kipps TJ, Keating MJ, Wierda WG: Increased expression of CD152 (CTLA-4) by normal T lymphocytes in untreated patients with B-cell chronic lymphocytic leukemia. Leukemia 19;1788-1793, 2005 https://doi.org/10.1038/sj.leu.2403907
  155. Beyer M, Kochanek M, Darabi K, Popov A, Jensen M, Edle E, Knolle PA, Thomas RK, von Bergwelt-Baildon M, Debey S, Hallek M, Schultze JL: Reduced frequencies and suppressive function of $CD4^{+}CD25^{hi}$ regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine. Blood 106;2018-2025, 2005 https://doi.org/10.1182/blood-2005-02-0642
  156. Wang X, Zheng J, Liu J, Yao J, He Y, Li X, Yu J, Yang J, Liu Z, Huang S: Increased population of CD4+$CD25^{high}$, regulatory T cells with their higher apoptotic and proliferating status in peripheral blood of acute myeloid leukemia patients. Eur J Haematol 75;468-476, 2005 https://doi.org/10.1111/j.1600-0609.2005.00537.x
  157. Szczepanski MJ, Szajnik M, Czystowska M, Mandapathil M, Strauss L, Welsh A, Foon KA, Whitside TL, Boyiadzis M: Increased frequency and suppression by regulatory T cells in patients with acute myelogenous leukemia. Clin Cancer Res 15;3325-3332, 2009 https://doi.org/10.1158/1078-0432.CCR-08-3010
  158. Carreras J, Lopez-Guillermo A, Fox BC, Coloomo L, Martinez A, Roncador G, Montserrat E, Campo E, Banham AH: High numbers of tumor-infiltrating FOXP3-positive regulatory T cells are associated with improved overall survival in follicular lymphoma. Blood 108;2957-2964, 2006 https://doi.org/10.1182/blood-2006-04-018218
  159. Yang ZZ, Novak AJ, Stenson MJ, Witzig TE, Ansell SM: Intratumoral CD4+CD25+regulatory T-cell-mediated suppression of infiltrating CD4+T-cells in B-cell non-Hodgkin lymphoma. Blood 107;3639-3646, 2006 https://doi.org/10.1182/blood-2005-08-3376
  160. Yang ZZ, Novak AJ, Ziesmer SC, Witzig TE, Ansell SM: Attenuation of CD8(+) T-cell function by CD4(+)CD25(+) regulatory T cells in B-cell non-Hodgkin's lymphoma. Cancer Res 66;10145-10152, 2006 https://doi.org/10.1158/0008-5472.CAN-06-1822
  161. Marshall NA, Christie LE, Munro LR, Culligan DJ, Johnston PW, Barker RN, Vickers MA: Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma. Blood 103;1755-1762, 2004 https://doi.org/10.1182/blood-2003-07-2594
  162. Alvaro T, Lejeune M, Salvado MT, Bosch R, Garcia JF, Jaen J, Banham AH, Roncador G, Montalban C, Piris MA: Outcome in Hodgkin's lymphoma can be predicted from the presence of accompanying cytotoxic and regulatory T cells. Clin Cancer Res 11;1467-1473, 2005 https://doi.org/10.1158/1078-0432.CCR-04-1869
  163. Baecher-Allan C, Viglietta V, Hafler DA: Human CD4+ CD25+ regulatory T cells. Semin Immunol 16;89-98, 2004 https://doi.org/10.1016/j.smim.2003.12.005
  164. Kosmaczewska A, Ciszak L, Potoczek S, Frydecka I: The significance of Treg cells in defective tumor immunity. Arch Immunol Ther EXp (Warsz) 56;181-191, 2008 https://doi.org/10.1007/s00005-008-0018-1
  165. Foss FM: DAB(389)IL-2 (ONTAK): a novel fusion toxin therapy for lymphoma. Clin Lymphoma 1;110-116, 2000 https://doi.org/10.3816/CLM.2000.n.009
  166. Wong BY, Gregory SA, Dang NH: Denileukin diftitox as novel targeted therapy for lymphoid malignancies. Cancer Invest 25;495-501, 2007 https://doi.org/10.1080/07357900701360096
  167. Chin KM, Foss FM: Biologic correlates of response and survival in patients with cutaneous T-cell lymphoma treated with denileukin diftitox. Clin Lymphoma Myeloma 7;199-204, 2006 https://doi.org/10.3816/CLM.2006.n.059
  168. Dannull J, Su Z, Rizzieri D, Yang BK, Coleman D, Yancey D, Zhang A, Dahm P, Chao N, Gilboa E, Vieweg J: Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells. J Clin Invest 115;3623-3633, 2005 https://doi.org/10.1172/JCI25947
  169. Foss F: Clinical experience with denileukin diftitox (ONTAK). Semin Oncol 33(1 Suppl 3);S11-16, 2006 https://doi.org/10.1053/j.seminoncol.2005.12.017
  170. Litzinger MT, Fernando R, Curiel TJ, Grosenbach DW, Schlom J, Palena C: IL-2 immunotoxin denileukin diftitox reduces regulatory T cells and enhances vaccine-mediated T-cell immunity. Blood 110;3192-3201, 2007 https://doi.org/10.1182/blood-2007-06-094615
  171. Powell DJ Jr, Attia P, Ghetie V, Schindler J, Vitetta ES, Rosenberg SA: Partial reduction of human FOXP3+ CD4 T cells in vivo after CD25-directed recombinant immunotoxin administration. J Immunother 31;189-198, 2008 https://doi.org/10.1097/CJI.0b013e31815dc0e8
  172. Olkhanud PB, Baatar D, Bodogai M, Hakim F, Gress R, Anderson RL, Deng J, Xu M, Briest S, Biragyn A: Breast cancer lung metastasis requires expression of chemokine receptor CCR4 and regulatory T cells. Cancer Res 69; 5996-6004, 2009 https://doi.org/10.1158/0008-5472.CAN-08-4619
  173. Curtin JF, Candolfi M, Fakhouri TM, Liu C, Alden A, Edwards M, Lowenstein PR, Castro MG: Treg depletion inhibits efficacy of cancer immunotherapy: implications for clinical trials. PLoS One 3;e1983, 2008 https://doi.org/10.1371/journal.pone.0001983
  174. Yang XF: Factors regulating apoptosis and homeostasis of CD4+ CD25(high) FOXP3+ regulatory T cells are new therapeutic targets. Front Biosci 13;1472-1499, 2008 https://doi.org/10.2741/2775
  175. Huang S: Regulation of metastases by signal transducer and activator of transcription 3 signaling pathway: clinical implications. Clin Cancer Res 13;1362-1366, 2007 https://doi.org/10.1158/1078-0432.CCR-06-2313
  176. Ling X, Arlinghaus RB: Knockdown of STAT3 expression by RNA interference inhibits the induction of breast tumors in immunocompetent mice. Cancer Res 65;2532-2536, 2005 https://doi.org/10.1158/0008-5472.CAN-04-2425
  177. Caramalho I, Lopes-Carvalho T, Ostler D, Zelenay S, Haury M, Demengeot J: Regulatory T cells selectively express toll-like receptors and are activated by lipopolysaccharide. J Exp Med 197;403-411, 2003 https://doi.org/10.1084/jem.20021633
  178. Peng G, Guo Z, Kiniwa Y, Voo KS, Peng W, Fu T, Wang DY, Li Y, Wang HY, Wang RF: Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function. Science 309;1380-1384, 2005 https://doi.org/10.1126/science.1113401
  179. Wang RF, Peng G, Wang HY: Regulatory T cells and Toll-like receptors in tumor immunity. Semin Immunol 18;136-142, 2006 https://doi.org/10.1016/j.smim.2006.01.008
  180. 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 65;794-802, 2004 https://doi.org/10.1016/j.humimm.2004.05.012
  181. Nair S, Boczkowski D, Fassnacht M, Pisetsky D, Gilboa E: Vaccination against the forkhead family transcription factor Foxp3 enhances tumor immunity. Cancer Res 67; 371-380, 2007 https://doi.org/10.1158/0008-5472.CAN-06-2903
  182. Francois V, Ottaviani S, Renkvist N, Stockis J, Schuler G, Thielemans K, Colau D, Marchand M, Boon T, Lucas S, van der Bruggen P: The CD4(+) T-cell response of melanoma patients to a MAGE-A3 peptide vaccine involves potential regulatory T cells. Cnacer Res 69;4335-4345, 2009 https://doi.org/10.1158/0008-5472.CAN-08-3726
  183. Jacob JB, Kong YC, Nalbantoglu I, Snower DP, Wei WZ: Tumor regression following DNA vaccination and regulatory T cell depletion in neu transgenic mice leads to an increased risk for autoimmunity. J Immunol 182;5873-5881, 2009 https://doi.org/10.4049/jimmunol.0804074
  184. Hiraoka N, Onozato K, Kosuge T, Hirohashi S: Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin Cancer Res 12;5423-5434, 2006 https://doi.org/10.1158/1078-0432.CCR-06-0369
  185. Shevach EM: Fatal attraction: tumors beckon regulatory T cells. Nat Med 10;900-901, 2004 https://doi.org/10.1038/nm0904-900
  186. Lu H: FOXP3 expression and prognosis: role of both the tumor and T cells. J Clin Oncol 27;1735-1736, 2009 https://doi.org/10.1200/JCO.2008.20.0675
  187. Kryczek I, Liu R, Wang G, Wu K, Shu X, Szeliga W, Vatan L, Finlayson E, Huang E, Simeone D, Redman B, Welling TH, Chang A, Zou W: FOXP3 defines regulatory T cells in human tumor and autoimmune disease. Cancer Res 69;3995-4000, 2009 https://doi.org/10.1158/0008-5472.CAN-08-3804
  188. Badoual C, Hans S, Fridman WH, Brasnu D, Erdman S, Tartour E: Revisiting the prognostic value of regulatory T cells in patients with cancer. J Clin Oncol 27;e5-6, 2009 https://doi.org/10.1200/JCO.2009.23.0680
  189. Badoual C, Hans S, Rodriguez J, Peyrard S, Klein C, Aqueznay Nel H, Mosseri V, Laccourreye O, Bruneval P, Fridman WH, Brasnu DF, Tartour E: Prognostic value of tumor-infiltrating CD4+ T-cell subpopulations in head and neck cancers. Clin Cancer Res 12;465-72, 2006 https://doi.org/10.1158/1078-0432.CCR-05-1886
  190. Wolf D, Rumpold H, Koppelstatter C, Gastl GA, Steurer M, Mayer G, Gunsilius E, Tilg H, Wolf AM: Telomere length of in vivo expanded CD4(+)CD25 (+) regulatory T-cells is preserved in cancer patients. Cancer Immunol Immunother 55;1198-1208, 2006 https://doi.org/10.1007/s00262-005-0107-5
  191. Elpek KG, Lacelle C, Singh NP, Yolcu ES, Shirwan H: CD4+CD25+ T regulatory cells dominate multiple immune evasion mechanisms in early but not late phases of tumor development in a B cell lymphoma model. J Immunol 178;6840-6848, 2007 https://doi.org/10.4049/jimmunol.178.11.6840
  192. Shafer-Weaver KA, Anderson MJ, Stagliano K, Malyguine A, Greenberg NM, Hurwitz AA: Cutting Edge: tumor-specific CD8+ T cells infiltrating prostatic tumors are induced to become suppressor cells. J Immunol 183; 4848-4852, 2009 https://doi.org/10.4049/jimmunol.0900848
  193. Petrausch U, Jensen SM, Twitty C, Poehlein CH, Haley DP, Walker EB, Fox BA: Disruption of TGF-beta signaling prevents the generation of tumor-sensitized regulatory T cells and facilitates therapeutic antitumor immunity. J Immunol 183;3682-3689, 2009 https://doi.org/10.4049/jimmunol.0900560
  194. Miyara M, Yoshioka Y, Kitoh A, Shima T, Wing K, Niwa A, Parizot C, Taflin C, Heike T, Valeyre D, Mathian A, Nakahata T, Yamaguchi T, Nomura T, Ono M, Amoura Z, Gorochov G, Sakaguchi S: Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 30;899-911, 2009 https://doi.org/10.1016/j.immuni.2009.03.019
  195. Ashley CW, Baecher-Allan C: Cutting Edge: responder T cells regulate human DR+ effector regulatory T cell activity via granzyme B. J Immunol 183;4843-4847, 2009 https://doi.org/10.4049/jimmunol.0900845
  196. Lu LF, Thai TH, Calado DP, Chaudhry A, Kubo M, Tanaka K, Loeb GB, Lee H, Yoshimura A, Rajewsky K, Rudensky AY: Foxp3-dependent microRNA155 confers competitive fitness to regulatory T cells by targeting SOCS1 protein. Immunity 30;80-91, 2009 https://doi.org/10.1016/j.immuni.2008.11.010
  197. Lodish HF, Zhou B, Liu G, Chen CZ: Micromanagement of the immune system by microRNAs. Nat Rev Immunol 8;120-130, 2008 https://doi.org/10.1038/nri2252
  198. Xiao C, Rajewsky K: MicroRNA control in the immune system: basic principles. Cell 136;26-36, 2009 https://doi.org/10.1016/j.cell.2008.12.027
  199. Lindsay MA: microRNAs and the immune response. Trends Immunol 29;343-351, 2008 https://doi.org/10.1016/j.it.2008.04.004
  200. Kohlhaas S, Garden OA, Scudamore C, Turner M, Okkenhaug K, Vigorito E: Cutting edge: the Foxp3 target miR-155 contributes to the development of regulatory T cells. J Immunol 182;2578-2582, 2009 https://doi.org/10.4049/jimmunol.0803162
  201. Ventura A, Jacks T: MicroRNAs and cancer: short RNAs go a long way. Cell 136;586-591, 2009 https://doi.org/10.1016/j.cell.2009.02.005

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