Skip to main content

Advertisement

Log in

Th17 cells: positive or negative role in tumor?

  • Review
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Th17 cells have been recently identified as a distinct Th cell lineage and found in an experimental animal model of cancer and in human cancers, but whether these cells promote tumor growth or regulate antitumor responses remains controversial. This review provides a summary of the current literature regarding interleukin (IL)-17/IL-23 and Th17 cells in cancer and discusses their potential roles in cancer development. Finally, we note several issues in this research area that must be resolved before the design of novel therapeutic approaches specifically targeting Th17 cells in cancer become feasible.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL (1986) Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 136:2348–2357

    CAS  PubMed  Google Scholar 

  2. Abbas AK, Murphy KM, Sher A (1996) Functional diversity of helper T lymphocytes. Nature 383:787–793

    Article  CAS  PubMed  Google Scholar 

  3. Murphy KM, Reiner SL (2002) The lineage decisions of helper T cells. Nat Rev Immunol 2:933–944

    Article  CAS  PubMed  Google Scholar 

  4. Romagnani S (1997) The Th1/Th2 paradigm. Immunol Today 18:263–266

    Article  CAS  PubMed  Google Scholar 

  5. Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, McGrady G, Wahl SM (2003) 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 198:1875–1886

    Article  CAS  PubMed  Google Scholar 

  6. Rudensky AY, Campbell DJ (2006) In vivo sites and cellular mechanisms of T reg cell-mediated suppression. J Exp Med 203:489–492

    Article  CAS  PubMed  Google Scholar 

  7. von Boehmer H (2005) Mechanisms of suppression by suppressor T cells. Nat Immunol 6:338–344

    Article  CAS  Google Scholar 

  8. Vignali DA, Collison LW, Workman CJ (2008) How regulatory T cells work. Nat Rev Immunol 8:523–532

    Article  CAS  PubMed  Google Scholar 

  9. Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4+ CD25+ regulatory T cells. Nat Immunol 4:330–336

    Article  CAS  PubMed  Google Scholar 

  10. Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, Lucian L, To W, Kwan S, Churakova T, Zurawski S, Wiekowski M, Lira SA, Gorman D, Kastelein RA, Sedgwick JD (2003) Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421:744–748

    Article  CAS  PubMed  Google Scholar 

  11. Murphy CA, Langrish CL, Chen Y, Blumenschein W, McClanahan T, Kastelein RA, Sedgwick JD, Cua DJ (2003) Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med 198:1951–1957

    Article  CAS  PubMed  Google Scholar 

  12. Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, Weaver CT (2005) Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 6:1123–1132

    Article  CAS  PubMed  Google Scholar 

  13. Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, Wang Y, Hood L, Zhu Z, Tian Q, Dong C (2005) A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 6:1133–1141

    Article  CAS  PubMed  Google Scholar 

  14. Acosta-Rodriguez EV, Rivino L, Geginat J, Jarrossay D, Gattorno M, Lanzavecchia A, Sallusto F, Napolitani G (2007) Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat Immunol 8:639–646

    Article  CAS  PubMed  Google Scholar 

  15. Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F (2007) Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol 8:942–949

    Article  CAS  PubMed  Google Scholar 

  16. Annunziato F, Cosmi L, Santarlasci V, Maggi L, Liotta F, Mazzinghi B, Parente E, Fili L, Ferri S, Frosali F, Giudici F, Romagnani P, Parronchi P, Tonelli F, Maggi E, Romagnani S (2007) Phenotypic and functional features of human Th17 cells. J Exp Med 204:1849–1861

    Article  CAS  PubMed  Google Scholar 

  17. Zhang GX, Gran B, Yu S, Li J, Siglienti I, Chen X, Kamoun M, Rostami A (2003) Induction of experimental autoimmune encephalomyelitis in IL-12 receptor-beta 2-deficient mice: IL-12 responsiveness is not required in the pathogenesis of inflammatory demyelination in the central nervous system. J Immunol 170:2153–2160

    CAS  PubMed  Google Scholar 

  18. Aggarwal S, Ghilardi N, Xie MH, de Sauvage FJ, Gurney AL (2003) Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem 278:1910–1914

    Article  CAS  PubMed  Google Scholar 

  19. Bettelli E, Oukka M, Kuchroo VK (2007) T-H-17 cells in the circle of immunity and autoimmunity. Nature Immunology 8:345–350

    Article  CAS  PubMed  Google Scholar 

  20. Dong C (2008) TH17 cells in development: an updated view of their molecular identity and genetic programming. Nat Rev Immunol 8:337–348

    Article  CAS  PubMed  Google Scholar 

  21. Weaver CT, Harrington LE, Mangan PR, Gavrieli M, Murphy KM (2006) Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 24:677–688

    Article  CAS  PubMed  Google Scholar 

  22. Dong G, Ye R, Shi W, Liu S, Wang T, Yang X, Yang N, Yu X (2003) IL-17 induces autoantibody overproduction and peripheral blood mononuclear cell overexpression of IL-6 in lupus nephritis patients. Chin Med J (Engl) 116:543–548

    CAS  Google Scholar 

  23. Tesmer LA, Lundy SK, Sarkar S, Fox DA (2008) Th17 cells in human disease. Immunol Rev 223:87–113

    Article  CAS  PubMed  Google Scholar 

  24. Traves SL, Donnelly LE (2008) Th17 cells in airway diseases. Curr Mol Med 8:416–426

    Article  CAS  PubMed  Google Scholar 

  25. Yamada H (2009) Th17 cells in human rheumatoid arthritis. Nihon Rinsho Meneki Gakkai Kaishi 32:249–255

    CAS  PubMed  Google Scholar 

  26. Oukka M (2008) Th17 cells in immunity and autoimmunity. Ann Rheum Dis 67(Suppl 3):iii26–iii29

    Google Scholar 

  27. Cooke A (2006) Th17 cells in inflammatory conditions. Rev Diabet Stud 3:72–75

    Article  PubMed  Google Scholar 

  28. Chen Z, Tato CM, Muul L, Laurence A, O’Shea JJ (2007) Distinct regulation of interleukin-17 in human T helper lymphocytes. Arthritis Rheum 56:2936–2946

    Article  CAS  PubMed  Google Scholar 

  29. Wilson NJ, Boniface K, Chan JR, McKenzie BS, Blumenschein WM, Mattson JD, Basham B, Smith K, Chen T, Morel F, Lecron JC, Kastelein RA, Cua DJ, McClanahan TK, Bowman EP, de Waal Malefyt R (2007) Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol 8:950–957

    Article  CAS  PubMed  Google Scholar 

  30. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441:235–238

    Article  CAS  PubMed  Google Scholar 

  31. Mangan PR, Harrington LE, O’Quinn DB, Helms WS, Bullard DC, Elson CO, Hatton RD, Wahl SM, Schoeb TR, Weaver CT (2006) Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 441:231–234

    Article  CAS  PubMed  Google Scholar 

  32. Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B (2006) TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24:179–189

    Article  CAS  PubMed  Google Scholar 

  33. Stritesky GL, Yeh N, Kaplan MH (2008) IL-23 promotes maintenance but not commitment to the Th17 lineage. J Immunol 181:5948–5955

    CAS  PubMed  Google Scholar 

  34. Chizzolini C, Chicheportiche R, Alvarez M, de Rham C, Roux-Lombard P, Ferrari-Lacraz S, Dayer JM (2008) Prostaglandin E2 synergistically with interleukin-23 favors human Th17 expansion. Blood 112:3696–3703

    Article  CAS  PubMed  Google Scholar 

  35. Manel N, Unutmaz D, Littman DR (2008) The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat Immunol 9:641–649

    Article  CAS  PubMed  Google Scholar 

  36. Yang L, Anderson DE, Baecher-Allan C, Hastings WD, Bettelli E, Oukka M, Kuchroo VK, Hafler DA (2008) IL-21 and TGF-beta are required for differentiation of human T(H)17 cells. Nature 454:350–352

    Article  CAS  PubMed  Google Scholar 

  37. Volpe E, Servant N, Zollinger R, Bogiatzi SI, Hupe P, Barillot E, Soumelis V (2008) A critical function for transforming growth factor-beta, interleukin 23 and proinflammatory cytokines in driving and modulating human T(H)-17 responses. Nat Immunol 9:650–657

    Article  CAS  PubMed  Google Scholar 

  38. Santarlasci V, Maggi L, Capone M, Frosali F, Querci V, De Palma R, Liotta F, Cosmi L, Maggi E, Romagnani S, Annunziato F (2009) TGF-beta indirectly favors the development of human Th17 cells by inhibiting Th1 cells. Eur J Immunol 39:207–215

    Article  CAS  PubMed  Google Scholar 

  39. Das J, Ren G, Zhang L, Roberts AI, Zhao X, Bothwell AL, Van Kaer L, Shi Y, Das G (2009) Transforming growth factor beta is dispensable for the molecular orchestration of Th17 cell differentiation. J Exp Med 206:2407–2416

    Article  CAS  PubMed  Google Scholar 

  40. Cosmi L, De Palma R, Santarlasci V, Maggi L, Capone M, Frosali F, Rodolico G, Querci V, Abbate G, Angeli R, Berrino L, Fambrini M, Caproni M, Tonelli F, Lazzeri E, Parronchi P, Liotta F, Maggi E, Romagnani S, Annunziato F (2008) Human interleukin 17-producing cells originate from a CD161+ CD4+ T cell precursor. J Exp Med 205:1903–1916

    Article  CAS  PubMed  Google Scholar 

  41. Zhou L, Ivanov II, Spolski R, Min R, Shenderov K, Egawa T, Levy DE, Leonard WJ, Littman DR (2007) IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol 8:967–974

    Article  CAS  PubMed  Google Scholar 

  42. Korn T, Bettelli E, Gao W, Awasthi A, Jager A, Strom TB, Oukka M, Kuchroo VK (2007) IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature 448:484–487

    Article  CAS  PubMed  Google Scholar 

  43. Nurieva R, Yang XO, Martinez G, Zhang Y, Panopoulos AD, Ma L, Schluns K, Tian Q, Watowich SS, Jetten AM, Dong C (2007) Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448:480–483

    Article  CAS  PubMed  Google Scholar 

  44. Laurence A, Tato CM, Davidson TS, Kanno Y, Chen Z, Yao Z, Blank RB, Meylan F, Siegel R, Hennighausen L, Shevach EM, O’Shea JJ (2007) Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 26:371–381

    Article  CAS  PubMed  Google Scholar 

  45. Gu Y, Yang J, Ouyang X, Liu W, Li H, Bromberg J, Chen SH, Mayer L, Unkeless JC, Xiong H (2008) Interleukin 10 suppresses Th17 cytokines secreted by macrophages and T cells. Eur J Immunol 38:1807–1813

    Article  CAS  PubMed  Google Scholar 

  46. Heo YJ, Joo YB, Oh HJ, Park MK, Heo YM, Cho ML, Kwok SK, Ju JH, Park KS, Cho SG, Park SH, Kim HY, Min JK (2010) IL-10 suppresses Th17 cells and promotes regulatory T cells in the CD4+ T cell population of rheumatoid arthritis patients. Immunol Lett 127:150–156

    Article  CAS  PubMed  Google Scholar 

  47. Batten M, Li J, Yi S, Kljavin NM, Danilenko DM, Lucas S, Lee J, de Sauvage FJ, Ghilardi N (2006) Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17-producing T cells. Nat Immunol 7:929–936

    Article  CAS  PubMed  Google Scholar 

  48. Stumhofer JS, Laurence A, Wilson EH, Huang E, Tato CM, Johnson LM, Villarino AV, Huang Q, Yoshimura A, Sehy D, Saris CJ, O’Shea JJ, Hennighausen L, Ernst M, Hunter CA (2006) Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system. Nat Immunol 7:937–945

    Article  CAS  PubMed  Google Scholar 

  49. Veldhoen M, Stockinger B (2006) TGFbeta1, a “Jack of all trades”: the link with pro-inflammatory IL-17-producing T cells. Trends Immunol 27:358–361

    Article  CAS  PubMed  Google Scholar 

  50. Akimzhanov AM, Yang XO, Dong C (2007) Chromatin remodeling of interleukin-17 (IL-17)-IL-17F cytokine gene locus during inflammatory helper T cell differentiation. J Biol Chem 282:5969–5972

    Article  CAS  PubMed  Google Scholar 

  51. Xu L, Kitani A, Fuss I, Strober W (2007) Cutting edge: regulatory T cells induce CD4+CD25-Foxp3- T cells or are self-induced to become Th17 cells in the absence of exogenous TGF-beta. J Immunol 178:6725–6729

    CAS  PubMed  Google Scholar 

  52. Koenen HJ, Smeets RL, Vink PM, van Rijssen E, Boots AM, Joosten I (2008) Human CD25highFoxp3pos regulatory T cells differentiate into IL-17-producing cells. Blood 112:2340–2352

    Article  CAS  PubMed  Google Scholar 

  53. Deknuydt F, Bioley G, Valmori D, Ayyoub M (2009) IL-1beta and IL-2 convert human Treg into T(H)17 cells. Clin Immunol 131:298–307

    Article  CAS  PubMed  Google Scholar 

  54. Ayyoub M, Deknuydt F, Raimbaud I, Dousset C, Leveque L, Bioley G, Valmori D (2009) Human memory FOXP3+ Tregs secrete IL-17 ex vivo and constitutively express the T(H)17 lineage-specific transcription factor RORgamma t. Proc Natl Acad Sci USA 106:8635–8640

    Article  CAS  PubMed  Google Scholar 

  55. Zhou L, Lopes JE, Chong MM, Ivanov II, Min R, Victora GD, Shen Y, Du J, Rubtsov YP, Rudensky AY, Ziegler SF, Littman DR (2008) TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 453:236–240

    Article  CAS  PubMed  Google Scholar 

  56. Du J, Huang C, Zhou B, Ziegler SF (2008) Isoform-specific inhibition of ROR alpha-mediated transcriptional activation by human FOXP3. J Immunol 180:4785–4792

    CAS  PubMed  Google Scholar 

  57. Yang XO, Nurieva R, Martinez GJ, Kang HS, Chung Y, Pappu BP, Shah B, Chang SH, Schluns KS, Watowich SS, Feng XH, Jetten AM, Dong C (2008) Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity 29:44–56

    Article  CAS  PubMed  Google Scholar 

  58. Voo KS, Wang YH, Santori FR, Boggiano C, Arima K, Bover L, Hanabuchi S, Khalili J, Marinova E, Zheng B, Littman DR, Liu YJ (2009) Identification of IL-17-producing FOXP3+ regulatory T cells in humans. Proc Natl Acad Sci USA 106:4793–4798

    Article  CAS  PubMed  Google Scholar 

  59. Annunziato F, Romagnani S (2009) Do studies in humans better depict Th17 cells? Blood 114:2213–2219

    Article  CAS  PubMed  Google Scholar 

  60. Lee YK, Turner H, Maynard CL, Oliver JR, Chen D, Elson CO, Weaver CT (2009) Late developmental plasticity in the T helper 17 lineage. Immunity 30:92–107

    Article  CAS  PubMed  Google Scholar 

  61. Bending D, De La Pena H, Veldhoen M, Phillips JM, Uyttenhove C, Stockinger B, Cooke A (2009) Highly purified Th17 cells from BDC2.5NOD mice convert into Th1-like cells in NOD/SCID recipient mice. J Clin Invest doi:10.1172/JCI37865

  62. Shi G, Cox CA, Vistica BP, Tan C, Wawrousek EF, Gery I (2008) Phenotype switching by inflammation-inducing polarized Th17 cells, but not by Th1 cells. J Immunol 181:7205–7213

    CAS  PubMed  Google Scholar 

  63. Amadi-Obi A, Yu CR, Liu X, Mahdi RM, Clarke GL, Nussenblatt RB, Gery I, Lee YS, Egwuagu CE (2007) TH17 cells contribute to uveitis and scleritis and are expanded by IL-2 and inhibited by IL-27/STAT1. Nat Med 13:711–718

    Article  CAS  PubMed  Google Scholar 

  64. van Beelen AJ, Zelinkova Z, Taanman-Kueter EW, Muller FJ, Hommes DW, Zaat SA, Kapsenberg ML, de Jong EC (2007) Stimulation of the intracellular bacterial sensor NOD2 programs dendritic cells to promote interleukin-17 production in human memory T cells. Immunity 27:660–669

    Article  PubMed  CAS  Google Scholar 

  65. Chen X, Vodanovic-Jankovic S, Johnson B, Keller M, Komorowski R, Drobyski WR (2007) Absence of regulatory T-cell control of TH1 and TH17 cells is responsible for the autoimmune-mediated pathology in chronic graft-versus-host disease. Blood 110:3804–3813

    Article  CAS  PubMed  Google Scholar 

  66. Loetscher P, Uguccioni M, Bordoli L, Baggiolini M, Moser B, Chizzolini C, Dayer JM (1998) CCR5 is characteristic of Th1 lymphocytes. Nature 391:344–345

    Article  CAS  PubMed  Google Scholar 

  67. Sallusto F, Lenig D, Mackay CR, Lanzavecchia A (1998) Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes. J Exp Med 187:875–883

    Article  CAS  PubMed  Google Scholar 

  68. Siveke JT, Hamann A (1998) T helper 1 and T helper 2 cells respond differentially to chemokines. J Immunol 160:550–554

    CAS  PubMed  Google Scholar 

  69. Bonecchi R, Bianchi G, Bordignon PP, D’Ambrosio D, Lang R, Borsatti A, Sozzani S, Allavena P, Gray PA, Mantovani A, Sinigaglia F (1998) Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s. J Exp Med 187:129–134

    Article  CAS  PubMed  Google Scholar 

  70. Annunziato F, Cosmi L, Liotta F, Maggi E, Romagnani S (2008) The phenotype of human Th17 cells and their precursors, the cytokines that mediate their differentiation and the role of Th17 cells in inflammation. Int Immunol 20:1361–1368

    Article  CAS  PubMed  Google Scholar 

  71. Rengarajan J, Szabo SJ, Glimcher LH (2000) Transcriptional regulation of Th1/Th2 polarization. Immunol Today 21:479–483

    Article  CAS  PubMed  Google Scholar 

  72. Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299:1057–1061

    Article  CAS  PubMed  Google Scholar 

  73. Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR (2006) The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126:1121–1133

    Article  CAS  PubMed  Google Scholar 

  74. Leppkes M, Becker C, Ivanov II, Hirth S, Wirtz S, Neufert C, Pouly S, Murphy AJ, Valenzuela DM, Yancopoulos GD, Becher B, Littman DR, Neurath MF (2009) RORgamma-expressing Th17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F. Gastroenterology 136:257–267

    Article  CAS  PubMed  Google Scholar 

  75. Crome SQ, Wang AY, Kang CY, Levings MK (2009) The role of retinoic acid-related orphan receptor variant 2 and IL-17 in the development and function of human CD4+ T cells. Eur J Immunol 39:1480–1493

    Article  CAS  PubMed  Google Scholar 

  76. Yang XO, Pappu BP, Nurieva R, Akimzhanov A, Kang HS, Chung Y, Ma L, Shah B, Panopoulos AD, Schluns KS, Watowich SS, Tian Q, Jetten AM, Dong C (2008) T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity 28:29–39

    Article  CAS  PubMed  Google Scholar 

  77. Yang XO, Panopoulos AD, Nurieva R, Chang SH, Wang D, Watowich SS, Dong C (2007) STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J Biol Chem 282:9358–9363

    Article  CAS  PubMed  Google Scholar 

  78. Egwuagu CE (2009) STAT3 in CD4+ T helper cell differentiation and inflammatory diseases. Cytokine 47:149–156

    Article  CAS  PubMed  Google Scholar 

  79. Mathur AN, Chang HC, Zisoulis DG, Stritesky GL, Yu Q, O’Malley JT, Kapur R, Levy DE, Kansas GS, Kaplan MH (2007) Stat3 and Stat4 direct development of IL-17-secreting Th cells. J Immunol 178:4901–4907

    CAS  PubMed  Google Scholar 

  80. Brustle A, Heink S, Huber M, Rosenplanter C, Stadelmann C, Yu P, Arpaia E, Mak TW, Kamradt T, Lohoff M (2007) The development of inflammatory T(H)-17 cells requires interferon-regulatory factor 4. Nat Immunol 8:958–966

    Article  PubMed  CAS  Google Scholar 

  81. Huber M, Brustle A, Reinhard K, Guralnik A, Walter G, Mahiny A, von Low E, Lohoff M (2008) IRF4 is essential for IL-21-mediated induction, amplification, and stabilization of the Th17 phenotype. Proc Natl Acad Sci USA 105:20846–20851

    Article  CAS  PubMed  Google Scholar 

  82. Chen Q, Yang W, Gupta S, Biswas P, Smith P, Bhagat G, Pernis AB (2008) IRF-4-binding protein inhibits interleukin-17 and interleukin-21 production by controlling the activity of IRF-4 transcription factor. Immunity 29:899–911

    Article  CAS  PubMed  Google Scholar 

  83. Veldhoen M, Hirota K, Westendorf AM, Buer J, Dumoutier L, Renauld JC, Stockinger B (2008) The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453:106–109

    Article  CAS  PubMed  Google Scholar 

  84. Veldhoen M, Hirota K, Christensen J, O’Garra A, Stockinger B (2009) Natural agonists for aryl hydrocarbon receptor in culture medium are essential for optimal differentiation of Th17 T cells. J Exp Med 206:43–49

    Article  CAS  PubMed  Google Scholar 

  85. Quintana FJ, Basso AS, Iglesias AH, Korn T, Farez MF, Bettelli E, Caccamo M, Oukka M, Weiner HL (2008) Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor. Nature 453:65–71

    Article  CAS  PubMed  Google Scholar 

  86. Moisan J, Grenningloh R, Bettelli E, Oukka M, Ho IC (2007) Ets-1 is a negative regulator of Th17 differentiation. J Exp Med 204:2825–2835

    Article  CAS  PubMed  Google Scholar 

  87. Chen Z, Laurence A, Kanno Y, Pacher-Zavisin M, Zhu BM, Tato C, Yoshimura A, Hennighausen L, O’Shea JJ (2006) Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells. Proc Natl Acad Sci USA 103:8137–8142

    Article  CAS  PubMed  Google Scholar 

  88. Kato T, Furumoto H, Ogura T, Onishi Y, Irahara M, Yamano S, Kamada M, Aono T (2001) Expression of IL-17 mRNA in ovarian cancer. Biochem Biophys Res Commun 282:735–738

    Article  CAS  PubMed  Google Scholar 

  89. Zhu X, Mulcahy LA, Mohammed RA, Lee AH, Franks HA, Kilpatrick L, Yilmazer A, Paish EC, Ellis IO, Patel PM, Jackson AM (2008) IL-17 expression by breast-cancer-associated macrophages: IL-17 promotes invasiveness of breast cancer cell lines. Breast Cancer Res 10:R95

    Article  PubMed  CAS  Google Scholar 

  90. Le Gouvello S, Bastuji-Garin S, Aloulou N, Mansour H, Chaumette MT, Berrehar F, Seikour A, Charachon A, Karoui M, Leroy K, Farcet JP, Sobhani I (2008) High prevalence of Foxp3 and IL17 in MMR-proficient colorectal carcinomas. Gut 57:772–779

    Article  CAS  PubMed  Google Scholar 

  91. Lee JW, Wang P, Kattah MG, Youssef S, Steinman L, DeFea K, Straus DS (2008) Differential regulation of chemokines by IL-17 in colonic epithelial cells. J Immunol 181:6536–6545

    CAS  PubMed  Google Scholar 

  92. Numasaki M, Watanabe M, Suzuki T, Takahashi H, Nakamura A, McAllister F, Hishinuma T, Goto J, Lotze MT, Kolls JK, Sasaki H (2005) IL-17 enhances the net angiogenic activity and in vivo growth of human non-small cell lung cancer in SCID mice through promoting CXCR-2-dependent angiogenesis. J Immunol 175:6177–6189

    CAS  PubMed  Google Scholar 

  93. Ciree A, Michel L, Camilleri-Broet S, Jean Louis F, Oster M, Flageul B, Senet P, Fossiez F, Fridman WH, Bachelez H, Tartour E (2004) Expression and activity of IL-17 in cutaneous T-cell lymphomas (mycosis fungoides and Sezary syndrome). Int J Cancer 112:113–120

    Article  CAS  PubMed  Google Scholar 

  94. Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, Vega F, Yu N, Wang J, Singh K, Zonin F, Vaisberg E, Churakova T, Liu M, Gorman D, Wagner J, Zurawski S, Liu Y, Abrams JS, Moore KW, Rennick D, de Waal-Malefyt R, Hannum C, Bazan JF, Kastelein RA (2000) Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 13:715–725

    Article  CAS  PubMed  Google Scholar 

  95. Langowski JL, Zhang X, Wu L, Mattson JD, Chen T, Smith K, Basham B, McClanahan T, Kastelein RA, Oft M (2006) IL-23 promotes tumour incidence and growth. Nature 442:461–465

    Article  CAS  PubMed  Google Scholar 

  96. Kryczek I, Wei S, Zou L, Altuwaijri S, Szeliga W, Kolls J, Chang A, Zou W (2007) Cutting edge: Th17 and regulatory T cell dynamics and the regulation by IL-2 in the tumor microenvironment. J Immunol 178:6730–6733

    CAS  PubMed  Google Scholar 

  97. Miyahara Y, Odunsi K, Chen W, Peng G, Matsuzaki J, Wang RF (2008) Generation and regulation of human CD4+ IL-17-producing T cells in ovarian cancer. Proc Natl Acad Sci USA 105:15505–15510

    Article  CAS  PubMed  Google Scholar 

  98. Su X, Ye J, Hsueh EC, Zhang Y, Hoft DF, Peng G (2010) Tumor microenvironments direct the recruitment and expansion of human Th17 cells. J Immunol 184:1630–1641

    Article  CAS  PubMed  Google Scholar 

  99. Zhang B, Rong G, Wei H, Zhang M, Bi J, Ma L, Xue X, Wei G, Liu X, Fang G (2008) The prevalence of Th17 cells in patients with gastric cancer. Biochem Biophys Res Commun 374:533–537

    Article  CAS  PubMed  Google Scholar 

  100. Zhang JP, Yan J, Xu J, Pang XH, Chen MS, Li L, Wu C, Li SP, Zheng L (2009) Increased intratumoral IL-17-producing cells correlate with poor survival in hepatocellular carcinoma patients. J Hepatol 50:980–989

    Article  CAS  PubMed  Google Scholar 

  101. Wu S, Rhee KJ, Albesiano E, Rabizadeh S, Wu X, Yen HR, Huso DL, Brancati FL, Wick E, McAllister F, Housseau F, Pardoll DM, Sears CL (2009) A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat Med 15:1016–1022

    Article  CAS  PubMed  Google Scholar 

  102. Alexandrakis MG, Pappa CA, Miyakis S, Sfiridaki A, Kafousi M, Alegakis A, Stathopoulos EN (2006) Serum interleukin-17 and its relationship to angiogenic factors in multiple myeloma. Eur J Intern Med 17:412–416

    Article  CAS  PubMed  Google Scholar 

  103. Dhodapkar KM, Barbuto S, Matthews P, Kukreja A, Mazumder A, Vesole D, Jagannath S, Dhodapkar MV (2008) Dendritic cells mediate the induction of polyfunctional human IL17-producing cells (Th17-1 cells) enriched in the bone marrow of patients with myeloma. Blood 112:2878–2885

    Article  CAS  PubMed  Google Scholar 

  104. Wu C, Wang S, Wang F, Chen Q, Peng S, Zhang Y, Qian J, Jin J, Xu H (2009) Increased frequencies of T helper type 17 cells in the peripheral blood of patients with acute myeloid leukaemia. Clin Exp Immunol 158:199–204

    Article  CAS  PubMed  Google Scholar 

  105. Kryczek I, Banerjee M, Cheng P, Vatan L, Szeliga W, Wei S, Huang E, Finlayson E, Simeone D, Welling TH, Chang A, Coukos G, Liu R, Zou W (2009) Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments. Blood 114:1141–1149

    Article  CAS  PubMed  Google Scholar 

  106. Yang ZZ, Novak AJ, Ziesmer SC, Witzig TE, Ansell SM (2009) Malignant B cells skew the balance of regulatory T cells and TH17 cells in B-cell non-Hodgkin’s lymphoma. Cancer Res 69:5522–5530

    Article  CAS  PubMed  Google Scholar 

  107. Horlock C, Stott B, Dyson PJ, Morishita M, Coombes RC, Savage P, Stebbing J (2009) The effects of trastuzumab on the CD4 + CD25 + FoxP3 + and CD4+ IL17A+ T-cell axis in patients with breast cancer. Br J Cancer 100:1061–1067

    Article  CAS  PubMed  Google Scholar 

  108. Kryczek I, Wei S, Szeliga W, Vatan L, Zou W (2009) Endogenous IL-17 contributes to reduced tumor growth and metastasis. Blood 114:357–359

    Article  CAS  PubMed  Google Scholar 

  109. Sfanos KS, Bruno TC, Maris CH, Xu L, Thoburn CJ, DeMarzo AM, Meeker AK, Isaacs WB, Drake CG (2008) Phenotypic analysis of prostate-infiltrating lymphocytes reveals TH17 and Treg skewing. Clin Cancer Res 14:3254–3261

    Article  CAS  PubMed  Google Scholar 

  110. Tartour E, Fossiez F, Joyeux I, Galinha A, Gey A, Claret E, Sastre-Garau X, Couturier J, Mosseri V, Vives V, Banchereau J, Fridman WH, Wijdenes J, Lebecque S, Sautes-Fridman C (1999) Interleukin 17, a T-cell-derived cytokine, promotes tumorigenicity of human cervical tumors in nude mice. Cancer Res 59:3698–3704

    CAS  PubMed  Google Scholar 

  111. Benchetrit F, Ciree A, Vives V, Warnier G, Gey A, Sautes-Fridman C, Fossiez F, Haicheur N, Fridman WH, Tartour E (2002) Interleukin-17 inhibits tumor cell growth by means of a T-cell-dependent mechanism. Blood 99:2114–2121

    Article  CAS  PubMed  Google Scholar 

  112. Lo CH, Lee SC, Wu PY, Pan WY, Su J, Cheng CW, Roffler SR, Chiang BL, Lee CN, Wu CW, Tao MH (2003) Antitumor and antimetastatic activity of IL-23. J Immunol 171:600–607

    CAS  PubMed  Google Scholar 

  113. Hu J, Yuan X, Belladonna ML, Ong JM, Wachsmann-Hogiu S, Farkas DL, Black KL, Yu JS (2006) Induction of potent antitumor immunity by intratumoral injection of interleukin 23-transduced dendritic cells. Can Res 66:8887–8896

    Article  CAS  Google Scholar 

  114. Kaiga T, Sato M, Kaneda H, Iwakura Y, Takayama T, Tahara H (2007) Systemic administration of IL-23 induces potent antitumor immunity primarily mediated through Th1-type response in association with the endogenously expressed IL-12. J Immunol 178:7571–7580

    CAS  PubMed  Google Scholar 

  115. Takahashi H, Numasaki M, Lotze MT, Sasaki H (2005) Interleukin-17 enhances bFGF-, HGF- and VEGF-induced growth of vascular endothelial cells. Immunol Lett 98:189–193

    Article  CAS  PubMed  Google Scholar 

  116. Numasaki M, Fukushi J, Ono M, Narula SK, Zavodny PJ, Kudo T, Robbins PD, Tahara H, Lotze MT (2003) Interleukin-17 promotes angiogenesis and tumor growth. Blood 101:2620–2627

    Article  CAS  PubMed  Google Scholar 

  117. Inozume T, Hanada K, Wang QJ, Yang JC (2009) IL-17 secreted by tumor reactive T cells induces IL-8 release by human renal cancer cells. J Immunother 32:109–117

    Article  CAS  PubMed  Google Scholar 

  118. Charles KA, Kulbe H, Soper R, Escorcio-Correia M, Lawrence T, Schultheis A, Chakravarty P, Thompson RG, Kollias G, Smyth JF, Balkwill FR, Hagemann T (2009) The tumor-promoting actions of TNF-alpha involve TNFR1 and IL-17 in ovarian cancer in mice and humans. J Clin Invest 119:3011–3023

    Article  CAS  PubMed  Google Scholar 

  119. Kuang DM, Peng C, Zhao Q, Wu Y, Chen MS, Zheng L (2010) Activated monocytes in peritumoral stroma of hepatocellular carcinoma promote expansion of memory T helper 17 cells. Hepatology 51:154–164

    Google Scholar 

  120. Antony PA, Piccirillo CA, Akpinarli A, Finkelstein SE, Speiss PJ, Surman DR, Palmer DC, Chan CC, Klebanoff CA, Overwijk WW, Rosenberg SA, Restifo NP (2005) 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

    CAS  PubMed  Google Scholar 

  121. Knutson KL, Disis ML, Salazar LG (2007) CD4 regulatory T cells in human cancer pathogenesis. Cancer Immunol Immunother 56:271–285

    Article  PubMed  Google Scholar 

  122. Leveque L, Deknuydt F, Bioley G, Old LJ, Matsuzaki J, Odunsi K, Ayyoub M, Valmori D (2009) Interleukin 2-mediated conversion of ovarian cancer-associated CD4+ regulatory T cells into proinflammatory interleukin 17-producing helper T cells. J Immunother 32:101–108

    Article  CAS  PubMed  Google Scholar 

  123. Vicari AP, Luu R, Zhang N, Patel S, Makinen SR, Hanson DC, Weeratna RD, Krieg AM (2009) Paclitaxel reduces regulatory T cell numbers and inhibitory function and enhances the anti-tumor effects of the TLR9 agonist PF-3512676 in the mouse. Cancer Immunol Immunother 58:615–628

    Article  CAS  PubMed  Google Scholar 

  124. Hirahara N, Nio Y, Sasaki S, Minari Y, Takamura M, Iguchi C, Dong M, Yamasawa K, Tamura K (2001) Inoculation of human interleukin-17 gene-transfected Meth-A fibrosarcoma cells induces T cell-dependent tumor-specific immunity in mice. Oncology 61:79–89

    Article  CAS  PubMed  Google Scholar 

  125. Benatar T, Cao MY, Lee Y, Li H, Feng N, Gu X, Lee V, Jin H, Wang M, Der S, Lightfoot J, Wright JA, Young AH (2008) Virulizin induces production of IL-17E to enhance antitumor activity by recruitment of eosinophils into tumors. Cancer Immunol Immunother 57:1757–1769

    Article  CAS  PubMed  Google Scholar 

  126. Benatar T, Cao MY, Lee Y, Lightfoot J, Feng N, Gu X, Lee V, Jin H, Wang M, Wright JA, Young AH (2009) IL-17E, a proinflammatory cytokine, has antitumor efficacy against several tumor types in vivo. Cancer Immunol Immunother doi:10.1007/s00262-009-0802-8

  127. Wang YQ, Ugai S, Shimozato O, Yu L, Kawamura K, Yamamoto H, Yamaguchi T, Saisho H, Tagawa M (2003) Induction of systemic immunity by expression of interleukin-23 in murine colon carcinoma cells. Int J Cancer 105:820–824

    Article  CAS  PubMed  Google Scholar 

  128. Kyte JA, Trachsel S, Risberg B, thor Straten P, Lislerud K, Gaudernack G (2009) Unconventional cytokine profiles and development of T cell memory in long-term survivors after cancer vaccination. Cancer Immunol Immunother 58:1609–1626

    Article  CAS  PubMed  Google Scholar 

  129. Martin-Orozco N, Muranski P, Chung Y, Yang XO, Yamazaki T, Lu S, Hwu P, Restifo NP, Overwijk WW, Dong C (2009) T helper 17 cells promote cytotoxic T cell activation in tumor immunity. Immunity 31:787–798

    Article  CAS  PubMed  Google Scholar 

  130. Muranski P, Boni A, Antony PA, Cassard L, Irvine KR, Kaiser A, Paulos CM, Palmer DC, Touloukian CE, Ptak K, Gattinoni L, Wrzesinski C, Hinrichs CS, Kerstann KW, Feigenbaum L, Chan CC, Restifo NP (2008) Tumor-specific Th17-polarized cells eradicate large established melanoma. Blood 112:362–373

    Article  CAS  PubMed  Google Scholar 

  131. von Euw E, Chodon T, Attar N, Jalil J, Koya RC, Comin-Anduix B, Ribas A (2009) CTLA4 blockade increases Th17 cells in patients with metastatic melanoma. J Transl Med 7:35

    Article  CAS  Google Scholar 

  132. Alvarez E, Moga E, Barquinero J, Sierra J, Briones J (2009) Dendritic and tumor cell fusions transduced with adenovirus encoding CD40L eradicate B-cell lymphoma and induce a Th17-type response. Gene Ther doi:10.1038/gt.2009.150

  133. Derhovanessian E, Adams V, Hahnel K, Groeger A, Pandha H, Ward S, Pawelec G (2009) Pretreatment frequency of circulating IL-17 + CD4 + T-cells, but not Tregs, correlates with clinical response to whole-cell vaccination in prostate cancer patients. Int J Cancer 125:1372–1379

    Article  CAS  PubMed  Google Scholar 

Download references

Conflict of interest statement

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Wanggang Zhang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ji, Y., Zhang, W. Th17 cells: positive or negative role in tumor?. Cancer Immunol Immunother 59, 979–987 (2010). https://doi.org/10.1007/s00262-010-0849-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-010-0849-6

Keywords

Navigation