Skip to main content

Regulatory T cells and immune tolerance to tumors

Immunologic Research volume 46, pages 79–93 (2010)Cite this article

Abstract

Immune cells infiltrate tumors and make up a significant component of the multicellular cancer micro-environment, yet the immune system often fails to prevent tumor formation and progression. One explanation for this paradox is the presence of tolerance-promoting regulatory T cells (Tregs) that counteract antitumor immune cells. Tregs were known to be essential for maintaining self-tolerance. Recently, Tregs have been found to promote tolerance to tumors in mouse models. Moreover, Treg infiltration in human tumors and malignant ascites is associated with worse clinical outcomes for various types of cancers. As many reviews have discussed the development and function of Tregs, this review focuses on the cellular and molecular mechanisms by which Tregs influence antitumor immune responses, and also discusses how these mechanisms might be exploited to develop innovative immune-based approaches that can improve cancer therapy.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1

References

  1. Dunn GP, Koebel CM, Schreiber RD. Interferons, immunity and cancer immunoediting. Nat Rev Immunol. 2006;6:836–48.

    PubMed  Google Scholar 

  2. Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE, Old LJ, et al. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature. 2001;410:1107–11.

    PubMed  Google Scholar 

  3. Smyth MJ, Crowe NY, Godfrey DI. NK cells and NKT cells collaborate in host protection from methylcholanthrene-induced fibrosarcoma. Int Immunol. 2001;13:459–63.

    PubMed  Google Scholar 

  4. Pardoll D. Does the immune system see tumors as foreign or self? Annu Rev Immunol. 2003;21:807–39.

    PubMed  Google Scholar 

  5. Dunn GP, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity. 2004;21:137–48.

    PubMed  Google Scholar 

  6. Gorelik L, Flavell RA. Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells. Nat Med. 2001;7:1118–22.

    PubMed  Google Scholar 

  7. Okada CY, Wong CP, Denney DW, Levy R. TCR vaccines for active immunotherapy of T cell malignancies. J Immunol. 1997;159:5516–27.

    PubMed  Google Scholar 

  8. Smyth MJ, Thia KY, Street SE, Cretney E, Trapani JA, Taniguchi M, et al. Differential tumor surveillance by natural killer (NK) and NKT cells. J Exp Med. 2000;191:661–8.

    PubMed  Google Scholar 

  9. Girardi M, Oppenheim DE, Steele CR, Lewis JM, Glusac E, Filler R, et al. Regulation of cutaneous malignancy by gammadelta T cells. Science. 2001;294:605–9.

    PubMed  Google Scholar 

  10. Kim S, Iizuka K, Aguila HL, Weissman IL, Yokoyama WM. In vivo natural killer cell activities revealed by natural killer cell-deficient mice. Proc Natl Acad Sci USA. 2000;97:2731–6.

    PubMed  Google Scholar 

  11. Dunn GP, Bruce AT, Sheehan KC, Shankaran V, Uppaluri R, Bui JD, et al. A critical function for type I interferons in cancer immunoediting. Nat Immunol. 2005;6:722–9.

    PubMed  Google Scholar 

  12. Lieberman J. The ABCs of granule-mediated cytotoxicity: new weapons in the arsenal. Nat Rev Immunol. 2003;3:361–70.

    PubMed  Google Scholar 

  13. Russell JH, Ley TJ. Lymphocyte-mediated cytotoxicity. Annu Rev Immunol. 2002;20:323–70.

    PubMed  Google Scholar 

  14. Rabinovich GA, Gabrilovich D, Sotomayor EM. Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol. 2007;25:267–96.

    PubMed  Google Scholar 

  15. Algarra I, Cabrera T, Garrido F. The HLA crossroad in tumor immunology. Hum Immunol. 2000;61:65–73.

    PubMed  Google Scholar 

  16. Marincola FM, Jaffee EM, Hicklin DJ, Ferrone S. Escape of human solid tumors from T-cell recognition: molecular mechanisms and functional significance. Adv Immunol. 2000;74:181–273.

    PubMed  Google Scholar 

  17. Seliger B, Maeurer MJ, Ferrone S. Antigen-processing machinery breakdown and tumor growth. Immunol Today. 2000;21:455–64.

    PubMed  Google Scholar 

  18. Bakker AB, Phillips JH, Figdor CG, Lanier LL. Killer cell inhibitory receptors for MHC class I molecules regulate lysis of melanoma cells mediated by NK cells, gamma delta T cells, and antigen-specific CTL. J Immunol. 1998;160:5239–45.

    PubMed  Google Scholar 

  19. Moretta A, Biassoni R, Bottino C, Pende D, Vitale M, Poggi A, et al. Major histocompatibility complex class I-specific receptors on human natural killer and T lymphocytes. Immunol Rev. 1997;155:105–17.

    PubMed  Google Scholar 

  20. Lanier LL, Phillips JH. Inhibitory MHC class I receptors on NK cells and T cells. Immunol Today. 1996;17:86–91.

    PubMed  Google Scholar 

  21. 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;155:1151–64.

    PubMed  Google Scholar 

  22. Sakaguchi S. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol. 2004;22:531–62.

    PubMed  Google Scholar 

  23. Yamaguchi T, Sakaguchi S. Regulatory T cells in immune surveillance and treatment of cancer. Semin Cancer Biol. 2006;16:115–23.

    PubMed  Google Scholar 

  24. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133:775–87.

    PubMed  Google Scholar 

  25. Zou W. Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol. 2006;6:295–307.

    PubMed  Google Scholar 

  26. von Boehmer H. Mechanisms of suppression by suppressor T cells. Nat Immunol. 2005;6:338–44.

    Google Scholar 

  27. Nagai H, Horikawa T, Hara I, Fukunaga A, Oniki S, Oka M, et al. In vivo elimination of CD25+ regulatory T cells leads to tumor rejection of B16F10 melanoma, when combined with interleukin-12 gene transfer. Exp Dermatol. 2004;13:613–20.

    PubMed  Google Scholar 

  28. 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. 1999;9:3128–33.

    Google Scholar 

  29. Shimizu J, Yamazaki S, Sakaguchi S. Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol. 1999;163:5211–8.

    PubMed  Google Scholar 

  30. 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. 2004;200:771–82.

    PubMed  Google Scholar 

  31. Antony PA, Piccirillo CA, Akpinarli A, Finkelstein SE, Speiss PJ, Surman DR, et al. 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. 2005;174:2591–601.

    PubMed  Google Scholar 

  32. Ghiringhelli F, Menard C, Terme M, Flament C, Taieb J, Chaput N, et al. CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor-beta-dependent manner. J Exp Med. 2005;202:1075–85.

    PubMed  Google Scholar 

  33. Curiel TJ. Tregs and rethinking cancer immunotherapy. J Clin Invest. 2007;117:1167–74.

    PubMed  Google Scholar 

  34. Nishizuka Y, Sakakura T. Thymus and reproduction: sex-linked dysgenesia of the gonad after neonatal thymectomy in mice. Science. 1969;166:753–5.

    PubMed  Google Scholar 

  35. Sakaguchi S, Takahashi T, Nishizuka Y. Study on cellular events in post-thymectomy autoimmune oophoritis in mice. II. Requirement of Lyt-1 cells in normal female mice for the prevention of oophoritis. J Exp Med. 1982;156:1577–86.

    PubMed  Google Scholar 

  36. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol. 2003;4:330–6.

    PubMed  Google Scholar 

  37. Gambineri E, Torgerson TR, Ochs HD. Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX), a syndrome of systemic autoimmunity caused by mutations of FOXP3, a critical regulator of T-cell homeostasis. Curr Opin Rheumatol. 2003;15:430–5.

    PubMed  Google Scholar 

  38. Brunkow ME, Jeffery EW, Hjerrild KA, Paeper B, Clark LB, Yasayko SA, et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet. 2001;27:68–73.

    PubMed  Google Scholar 

  39. 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;389:737–42.

    PubMed  Google Scholar 

  40. Vieira PL, Christensen JR, Minaee S, O’Neill EJ, Barrat FJ, Boonstra A, et al. IL-10-secreting regulatory T cells do not express Foxp3 but have comparable regulatory function to naturally occurring CD4+CD25+ regulatory T cells. J Immunol. 2004;172:5986–93.

    PubMed  Google Scholar 

  41. Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, et al. Conversion of peripheral CD4+CD25− naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med. 2003;198:1875–86.

    PubMed  Google Scholar 

  42. Apostolou I, von Boehmer H. In vivo instruction of suppressor commitment in naive T cells. J Exp Med. 2004;199:1401–8.

    PubMed  Google Scholar 

  43. Skapenko A, Kalden JR, Lipsky PE, Schulze-Koops H. The IL-4 receptor alpha-chain-binding cytokines, IL-4 and IL-13, induce forkhead box P3-expressing CD25+CD4+ regulatory T cells from CD25−CD4+ precursors. J Immunol. 2005;175:6107–16.

    PubMed  Google Scholar 

  44. Hahn BH, Singh RP, La Cava A, Ebling FM. Tolerogenic treatment of lupus mice with consensus peptide induces Foxp3-expressing, apoptosis-resistant, TGFbeta-secreting CD8+ T cell suppressors. J Immunol. 2005;175:7728–37.

    PubMed  Google Scholar 

  45. Gilliet M, Liu YJ. Generation of human CD8 T regulatory cells by CD40 ligand-activated plasmacytoid dendritic cells. J Exp Med. 2002;195:695–704.

    PubMed  Google Scholar 

  46. Wei S, Kryczek I, Zou L, Daniel B, Cheng P, Mottram P, et al. Plasmacytoid dendritic cells induce CD8+ regulatory T cells in human ovarian carcinoma. Cancer Res. 2005;65:5020–6.

    PubMed  Google Scholar 

  47. Haribhai D, Lin W, Relland LM, Truong N, Williams CB, Chatila TA. Regulatory T cells dynamically control the primary immune response to foreign antigen. J Immunol. 2007;178:2961–72.

    PubMed  Google Scholar 

  48. Chen W, Zhou D, Torrealba JR, Waddell TK, Grant D, Zhang L. Donor lymphocyte infusion induces long-term donor-specific cardiac xenograft survival through activation of recipient double-negative regulatory T cells. J Immunol. 2005;175:3409–16.

    PubMed  Google Scholar 

  49. Fischer K, Voelkl S, Heymann J, Przybylski GK, Mondal K, Laumer M, et al. Isolation and characterization of human antigen-specific TCR alpha beta+ CD4(−)CD8− double-negative regulatory T cells. Blood. 2005;105:2828–35.

    PubMed  Google Scholar 

  50. Peng G, Wang HY, Peng W, Kiniwa Y, Seo KH, Wang RF. Tumor-infiltrating gammadelta T cells suppress T and dendritic cell function via mechanisms controlled by a unique toll-like receptor signaling pathway. Immunity. 2007;27:334–48.

    PubMed  Google Scholar 

  51. Gajewski TF. The expanding universe of regulatory T cell subsets in cancer. Immunity. 2007;27:185–7.

    PubMed  Google Scholar 

  52. Kuhn R, Lohler J, Rennick D, Rajewsky K, Muller W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell. 1993;75:263–74.

    PubMed  Google Scholar 

  53. Kulkarni AB, Huh CG, Becker D, Geiser A, Lyght M, Flanders KC, et al. Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci USA. 1993;90:770–4.

    PubMed  Google Scholar 

  54. Maloy KJ, Salaun L, Cahill R, Dougan G, Saunders NJ, Powrie F. CD4+CD25+ T(R) cells suppress innate immune pathology through cytokine-dependent mechanisms. J Exp Med. 2003;197:111–9.

    PubMed  Google Scholar 

  55. Mottet C, Uhlig HH, Powrie F. Cutting edge: cure of colitis by CD4+CD25+ regulatory T cells. J Immunol. 2003;170:3939–43.

    PubMed  Google Scholar 

  56. Akbari O, Freeman GJ, Meyer EH, Greenfield EA, Chang TT, Sharpe AH, et al. Antigen-specific regulatory T cells develop via the ICOS-ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity. Nat Med. 2002;8:1024–32.

    PubMed  Google Scholar 

  57. Ostroukhova M, Seguin-Devaux C, Oriss TB, Dixon-McCarthy B, Yang L, Ameredes BT, et al. Tolerance induced by inhaled antigen involves CD4(+) T cells expressing membrane-bound TGF-beta and FOXP3. J Clin Invest. 2004;114:28–38.

    PubMed  Google Scholar 

  58. Workman CJ, Szymczak-Workman AL, Collison LW, Pillai MR, Vignali DA. The development and function of regulatory T cells. Cell Mol Life Sci. 2009;66:2603–22.

    PubMed  Google Scholar 

  59. You S, Leforban B, Garcia C, Bach JF, Bluestone JA, Chatenoud L. Adaptive TGF-beta-dependent regulatory T cells control autoimmune diabetes and are a privileged target of anti-CD3 antibody treatment. Proc Natl Acad Sci USA. 2007;104:6335–40.

    PubMed  Google Scholar 

  60. You S, Alyanakian MA, Segovia B, Damotte D, Bluestone J, Bach JF, et al. Immunoregulatory pathways controlling progression of autoimmunity in NOD mice. Ann NY Acad Sci. 2008;1150:300–10.

    PubMed  Google Scholar 

  61. Loser K, Apelt J, Voskort M, Mohaupt M, Balkow S, Schwarz T, et al. IL-10 controls ultraviolet-induced carcinogenesis in mice. J Immunol. 2007;179:365–71.

    PubMed  Google Scholar 

  62. Chen ML, Pittet MJ, Gorelik L, Flavell RA, Weissleder R, von Boehmer H, et al. Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-beta signals in vivo. Proc Natl Acad Sci USA. 2005;102:419–24.

    PubMed  Google Scholar 

  63. Gil-Guerrero L, Dotor J, Huibregtse IL, Casares N, Lopez-Vazquez AB, Rudilla F, et al. In vitro and in vivo down-regulation of regulatory T cell activity with a peptide inhibitor of TGF-beta1. J Immunol. 2008;181:126–35.

    PubMed  Google Scholar 

  64. Strauss L, Bergmann C, Szczepanski M, Gooding W, Johnson JT, Whiteside TL. A unique subset of CD4+CD25 high Foxp3+ T cells secreting interleukin-10 and transforming growth factor-beta1 mediates suppression in the tumor microenvironment. Clin Cancer Res. 2007;13:4345–54.

    PubMed  Google Scholar 

  65. Collison LW, Workman CJ, Kuo TT, Boyd K, Wang Y, Vignali KM, et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature. 2007;450:566–9.

    PubMed  Google Scholar 

  66. Bardel E, Larousserie F, Charlot-Rabiega P, Coulomb-L’Hermine A, Devergne O. Human CD4+CD25+Foxp3+ regulatory T cells do not constitutively express IL-35. J Immunol. 2008;181:6898–905.

    PubMed  Google Scholar 

  67. Smyth MJ, Thia KY, Street SE, MacGregor D, Godfrey DI, Trapani JA. Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma. J Exp Med. 2000;192:755–60.

    PubMed  Google Scholar 

  68. Grossman WJ, Verbsky JW, Barchet W, Colonna M, Atkinson JP, Ley TJ. Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity. 2004;21:589–601.

    PubMed  Google Scholar 

  69. Gondek DC, Lu LF, Quezada SA, Sakaguchi S, Noelle RJ. Cutting edge: contact-mediated suppression by CD4+CD25+ regulatory cells involves a granzyme B-dependent, perforin-independent mechanism. J Immunol. 2005;174:1783–6.

    PubMed  Google Scholar 

  70. Zhao DM, Thornton AM, DiPaolo RJ, Shevach EM. Activated CD4+CD25+ T cells selectively kill B lymphocytes. Blood. 2006;107:3925–32.

    PubMed  Google Scholar 

  71. Cao X, Cai SF, Fehniger TA, Song J, Collins LI, Piwnica-Worms DR, et al. Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance. Immunity. 2007;27:635–46.

    PubMed  Google Scholar 

  72. Gondek DC, Devries V, Nowak EC, Lu LF, Bennett KA, Scott ZA, et al. Transplantation survival is maintained by granzyme B+ regulatory cells and adaptive regulatory T cells. J Immunol. 2008;181:4752–60.

    PubMed  Google Scholar 

  73. Strauss L, Bergmann C, Whiteside TL. Human circulating CD4+CD25 high Foxp3+ regulatory T cells kill autologous CD8+ but not CD4+ responder cells by Fas-mediated apoptosis. J Immunol. 2009;182:1469–80.

    PubMed  Google Scholar 

  74. Ren X, Ye F, Jiang Z, Chu Y, Xiong S, Wang Y. Involvement of cellular death in TRAIL/DR5-dependent suppression induced by CD4(+)CD25(+) regulatory T cells. Cell Death Differ. 2007;14:2076–84.

    PubMed  Google Scholar 

  75. Tang Q, Adams JY, Tooley AJ, Bi M, Fife BT, Serra P, et al. Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice. Nat Immunol. 2006;7:83–92.

    PubMed  Google Scholar 

  76. Tadokoro CE, Shakhar G, Shen S, Ding Y, Lino AC, Maraver A, et al. Regulatory T cells inhibit stable contacts between CD4+ T cells and dendritic cells in vivo. J Exp Med. 2006;203:505–11.

    PubMed  Google Scholar 

  77. Read S, Malmstrom V, Powrie F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J Exp Med. 2000;192:295–302.

    PubMed  Google Scholar 

  78. Oderup C, Cederbom L, Makowska A, Cilio CM, Ivars F. Cytotoxic T lymphocyte antigen-4-dependent down-modulation of costimulatory molecules on dendritic cells in CD4+CD25+ regulatory T-cell-mediated suppression. Immunology. 2006;118:240–9.

    PubMed  Google Scholar 

  79. 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;322:271–5.

    PubMed  Google Scholar 

  80. Mellor AL, Munn DH. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol. 2004;4:762–74.

    PubMed  Google Scholar 

  81. Munn DH, Shafizadeh E, Attwood JT, Bondarev I, Pashine A, Mellor AL. Inhibition of T cell proliferation by macrophage tryptophan catabolism. J Exp Med. 1999;189:1363–72.

    PubMed  Google Scholar 

  82. Fallarino F, Grohmann U, Vacca C, Bianchi R, Orabona C, Spreca A, et al. T cell apoptosis by tryptophan catabolism. Cell Death Differ. 2002;9:1069–77.

    PubMed  Google Scholar 

  83. Sharma MD, Baban B, Chandler P, Hou DY, Singh N, Yagita H, et al. Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2, 3-dioxygenase. J Clin Invest. 2007;117:2570–82.

    PubMed  Google Scholar 

  84. Vignali DA, Collison LW, Workman CJ. How regulatory T cells work. Nat Rev Immunol. 2008;8:523–32.

    PubMed  Google Scholar 

  85. Bopp T, Becker C, Klein M, Klein-Hessling S, Palmetshofer A, Serfling E, et al. Cyclic adenosine monophosphate is a key component of regulatory T cell-mediated suppression. J Exp Med. 2007;204:1303–10.

    PubMed  Google Scholar 

  86. 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;8:1353–62.

    PubMed  Google Scholar 

  87. Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 2004;10:942–9.

    PubMed  Google Scholar 

  88. 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;102:18538–43.

    PubMed  Google Scholar 

  89. Nishikawa H, Kato T, Tawara I, Takemitsu T, Saito K, Wang L, et al. Accelerated chemically induced tumor development mediated by CD4+CD25+ regulatory T cells in wild-type hosts. Proc Natl Acad Sci USA. 2005;102:9253–7.

    PubMed  Google Scholar 

  90. Mizukami Y, Kono K, Kawaguchi Y, Akaike H, Kamimura K, Sugai H, et al. CCL17 and CCL22 chemokines within tumor microenvironment are related to accumulation of Foxp3+ regulatory T cells in gastric cancer. Int J Cancer. 2008;122:2286–93.

    PubMed  Google Scholar 

  91. Gobert M, Treilleux I, Bendriss-Vermare N, Bachelot T, Goddard-Leon S, Arfi V, et al. 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. 2009;69:2000–9.

    PubMed  Google Scholar 

  92. Zhou G, Drake CG, Levitsky HI. Amplification of tumor-specific regulatory T cells following therapeutic cancer vaccines. Blood. 2006;107:628–36.

    PubMed  Google Scholar 

  93. Hsieh CS, Zheng Y, Liang Y, Fontenot JD, Rudensky AY. An intersection between the self-reactive regulatory and nonregulatory T cell receptor repertoires. Nat Immunol. 2006;7:401–10.

    PubMed  Google Scholar 

  94. Hsieh CS, Liang Y, Tyznik AJ, Self SG, Liggitt D, Rudensky AY. Recognition of the peripheral self by naturally arising CD25+CD4+ T cell receptors. Immunity. 2004;21:267–77.

    PubMed  Google Scholar 

  95. Tang Q, Henriksen KJ, Bi M, Finger EB, Szot G, Ye J, et al. In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J Exp Med. 2004;199:1455–65.

    PubMed  Google Scholar 

  96. Jaeckel E, von Boehmer H, Manns MP. Antigen-specific FoxP3-transduced T-cells can control established type 1 diabetes. Diabetes. 2005;54:306–10.

    PubMed  Google Scholar 

  97. Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol. 2005;6:1142–51.

    PubMed  Google Scholar 

  98. Thornton AM, Piccirillo CA, Shevach EM. Activation requirements for the induction of CD4+CD25+ T cell suppressor function. Eur J Immunol. 2004;34:366–76.

    PubMed  Google Scholar 

  99. Lio CW, Hsieh CS. A two-step process for thymic regulatory T cell development. Immunity. 2008;28:100–11.

    PubMed  Google Scholar 

  100. Burchill MA, Yang J, Vang KB, Moon JJ, Chu HH, Lio CW, et al. Linked T cell receptor and cytokine signaling govern the development of the regulatory T cell repertoire. Immunity. 2008;28:112–21.

    PubMed  Google Scholar 

  101. Ghiringhelli F, Puig PE, Roux S, Parcellier A, Schmitt E, Solary E, et al. Tumor cells convert immature myeloid dendritic cells into TGF-beta-secreting cells inducing CD4+CD25+ regulatory T cell proliferation. J Exp Med. 2005;202:919–29.

    PubMed  Google Scholar 

  102. Dougan M, Dranoff G. Immune therapy for cancer. Annu Rev Immunol. 2009;27:83–117.

    PubMed  Google Scholar 

  103. Duvic M, Talpur R. Optimizing denileukin diftitox (Ontak) therapy. Future Oncol. 2008;4:457–69.

    PubMed  Google Scholar 

  104. Dannull J, Su Z, Rizzieri D, Yang BK, Coleman D, Yancey D, et al. Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells. J Clin Invest. 2005;115:3623–33.

    PubMed  Google Scholar 

  105. Weber J. Overcoming immunologic tolerance to melanoma: targeting CTLA-4 with ipilimumab (MDX-010). Oncologist. 2008;13(Suppl 4):16–25.

    PubMed  Google Scholar 

  106. Tang Q, Bluestone JA. The Foxp3+ regulatory T cell: a jack of all trades, master of regulation. Nat Immunol. 2008;9:239–44.

    PubMed  Google Scholar 

Download references

Author information

Affiliations

  1. Department of Immunology, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY, 14263, USA

    Xuefang Cao

Authors
  1. Xuefang Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xuefang Cao.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Cao, X. Regulatory T cells and immune tolerance to tumors. Immunol Res 46, 79–93 (2010). https://doi.org/10.1007/s12026-009-8124-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12026-009-8124-7

Keywords

  • Regulatory T cells (Tregs)
  • Self-tolerance
  • Tumor immunity
  • Tumor micro-environment
  • Immunotherapy