Skip to main content
SpringerLink
Log in

IL-9 and Th9 Cells in Tumor Immunity

  • Chapter
  • First Online:
Tumor Microenvironment

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1240))

Abstract

T cells can be categorized into functionally diverse subpopulations, which include Th1, Th2, Th9, Th17, Th22, and Tfh cells and Foxp3+ Tregs, based on their role in maintaining normal immune homeostasis and affecting pathological immune-associated diseases. Among these subpopulations, Th9 cells are relatively new, and less is known about their signaling and effects on tumor immunity. Recently, some studies have focused on regulation of the IL-9/IL-9R signaling pathway and Th9 cell differentiation and their roles in tumor environments. Herein, we summarize recent progress in understanding the regulatory signaling of IL-9 and Th9 cells and their critical roles and mechanisms in antitumor immunity.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

AKT:

Protein kinase B

ALCL:

Anaplastic large cell lymphoma

Bcl6:

B cell lymphoma 6

CTL:

Cytotoxic lymphocyte

DCs:

Dendritic cells

EAE:

Experimental autoimmune encephalitis

FOXO1:

Forkhead box protein O1

GATA3:

GATA binding protein 3

GITR:

TNF receptor-related protein

GrzB:

Granzyme B

HAT:

Histone acetyltransferase

HIF1α:

Hypoxia-inducible factor-1α

HTLV-1:

Human cell leukemia virus 1

IFNγ:

Interferon-γ

IL-9:

Interleukin 9

IL-9R:

IL-9 receptor

MAPK:

Mitogen-activated protein kinase

mTOR:

Mechanistic target of rapamycin

NFAT:

Nuclear factor of activated T cells

NF-kB:

Nuclear factor-kappa B

NK cells:

Natural killer cells

NKT cells:

Natural killer T cells

PI-3K:

Phosphatidylinositol 3′-kinase

rIL-9:

Recombinant IL-9 protein

STAT6:

Signal transducer and activator of transcription 6

TAK1:

Transforming growth factor-activated kinase-1

T-bet:

T-box transcription factor

Tc9:

IL-9-producing CD8+ T cells

Tfh cells:

T follicular helper cells

TGFβ1:

Transforming growth factor-β1

Th:

T helper cells

Th1:

IFNγ-producing CD4+ T cells

Th9:

IL-9-producing CD4+ T cells

TNFα:

Tumor necrosis factor-α

Treg cells:

Regulatory T cells

TSLP:

Thymic stromal lymphopoietin

References

  1. Van Snick J, Goethals A, Renauld JC, Van Roost E, Uyttenhove C, Rubira MR et al (1989) Cloning and characterization of a cDNA for a new mouse T cell growth factor (P40). J Exp Med 169(1):363–368

    Article  PubMed  Google Scholar 

  2. Mock BA, Krall M, Kozak CA, Nesbitt MN, McBride OW, Renauld JC et al (1990) IL9 maps to mouse chromosome 13 and human chromosome 5. Immunogenetics 31(4):265–270

    Article  CAS  PubMed  Google Scholar 

  3. Kaplan MH, Hufford MM, Olson MR (2015) The development and in vivo function of T helper 9 cells. Nat Rev Immunol 15(5):295–307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Goswami R, Kaplan MH (2011) A brief history of IL-9. J Immunol 186(6):3283–3288

    Article  CAS  PubMed  Google Scholar 

  5. Rojas-Zuleta WG, Vasquez G (2016) Th9 lymphocytes: a recent history from IL-9 to its potential role in rheumatic diseases. Autoimmun Rev 15(7):649–655

    Article  CAS  PubMed  Google Scholar 

  6. Demoulin JB, Uyttenhove C, Van Roost E, DeLestre B, Donckers D, Van Snick J et al (1996) A single tyrosine of the interleukin-9 (IL-9) receptor is required for STAT activation, antiapoptotic activity, and growth regulation by IL-9. Mol Cell Biol 16(9):4710–4716

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Vermeesch JR, Petit P, Kermouni A, Renauld JC, Van Den Berghe H, Marynen P (1997) The IL-9 receptor gene, located in the Xq/Yq pseudoautosomal region, has an autosomal origin, escapes X inactivation and is expressed from the Y. Hum Mol Genet 6(1):1–8

    Article  CAS  PubMed  Google Scholar 

  8. Knoops L, Renauld JC (2004) IL-9 and its receptor: from signal transduction to tumorigenesis. Growth Factors 22(4):207–215

    Article  CAS  PubMed  Google Scholar 

  9. Fawaz LM, Sharif-Askari E, Hajoui O, Soussi-Gounni A, Hamid Q, Mazer BD (2007) Expression of IL-9 receptor alpha chain on human germinal center B cells modulates IgE secretion. J Allergy Clin Immunol 120(5):1208–1215

    Article  CAS  PubMed  Google Scholar 

  10. Nalleweg N, Chiriac MT, Podstawa E, Lehmann C, Rau TT, Atreya R et al (2015) IL-9 and its receptor are predominantly involved in the pathogenesis of UC. Gut 64(5):743–755

    Article  CAS  PubMed  Google Scholar 

  11. Fontaine RH, Cases O, Lelievre V, Mesples B, Renauld JC, Loron G et al (2008) IL-9/IL-9 receptor signaling selectively protects cortical neurons against developmental apoptosis. Cell Death Differ 15(10):1542–1552

    Article  CAS  PubMed  Google Scholar 

  12. Hong CH, Chang KL, Wang HJ, Yu HS, Lee CH (2015) IL-9 induces IL-8 production via STIM1 activation and ERK phosphorylation in epidermal keratinocytes: a plausible mechanism of IL-9R in atopic dermatitis. J Dermatol Sci 78(3):206–214

    Article  CAS  PubMed  Google Scholar 

  13. Malik S, Sadhu S, Elesela S, Pandey RP, Chawla AS, Sharma D et al (2017) Transcription factor Foxo1 is essential for IL-9 induction in T helper cells. Nat Commun 8(1):815

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Bi E, Ma X, Lu Y, Yang M, Wang Q, Xue G et al (2017) Foxo1 and Foxp1 play opposing roles in regulating the differentiation and antitumor activity of TH9 cells programmed by IL-7. Sci Signal 10(500)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Martelli AM, Tabellini G, Ricci F, Evangelisti C, Chiarini F, Bortul R et al (2012) PI3K/AKT/mTORC1 and MEK/ERK signaling in T-cell acute lymphoblastic leukemia: new options for targeted therapy. Adv Biol Regul 52(1):214–227

    Article  CAS  PubMed  Google Scholar 

  16. Li Y, Yu Q, Zhang Z, Wang J, Li S, Zhang J et al (2016) TH9 cell differentiation, transcriptional control and function in inflammation, autoimmune diseases and cancer. Oncotarget 7(43):71001–71012

    PubMed  PubMed Central  Google Scholar 

  17. Gorczynski R, Yu K, Chen Z (2014) Anti-CD200R2, anti-IL-9, anti-IL-35, or anti-TGF-beta abolishes increased graft survival and Treg induction induced in cromolyn-treated CD200R1KO.CD200tg mice. Transplantation 97(1):39–46

    Article  CAS  PubMed  Google Scholar 

  18. Schmitt E, Germann T, Goedert S, Hoehn P, Huels C, Koelsch S et al (1994) IL-9 production of naive CD4+ T cells depends on IL-2, is synergistically enhanced by a combination of TGF-beta and IL-4, and is inhibited by IFN-gamma. J Immunol 153(9):3989–3996

    CAS  PubMed  Google Scholar 

  19. Gerlach K, Hwang Y, Nikolaev A, Atreya R, Dornhoff H, Steiner S et al (2014) TH9 cells that express the transcription factor PU.1 drive T cell-mediated colitis via IL-9 receptor signaling in intestinal epithelial cells. Nat Immunol 15(7):676–686

    Article  CAS  PubMed  Google Scholar 

  20. Gomez-Rodriguez J, Meylan F, Handon R, Hayes ET, Anderson SM, Kirby MR et al (2016) Itk is required for Th9 differentiation via TCR-mediated induction of IL-2 and IRF4. Nat Commun 7:10857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Veldhoen M, Uyttenhove C, van Snick J, Helmby H, Westendorf A, Buer J et al (2008) Transforming growth factor-beta ‘reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat Immunol 9(12):1341–1346

    Article  CAS  PubMed  Google Scholar 

  22. Jabeen R, Goswami R, Awe O, Kulkarni A, Nguyen ET, Attenasio A et al (2013) Th9 cell development requires a BATF-regulated transcriptional network. J Clin Invest 123(11):4641–4653

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wang Y, Bi Y, Chen X, Li C, Li Y, Zhang Z et al (2016) Histone deacetylase SIRT1 negatively regulates the differentiation of interleukin-9-producing CD4(+) T cells. Immunity 44(6):1337–1349

    Article  CAS  PubMed  Google Scholar 

  24. Micosse C, von Meyenn L, Steck O, Kipfer E, Adam C, Simillion C et al (2019) Human “TH9” cells are a subpopulation of PPAR-gamma(+) TH2 cells. Sci Immunol 4(31)

    Google Scholar 

  25. Goswami R, Jabeen R, Yagi R, Pham D, Zhu J, Goenka S et al (2012) STAT6-dependent regulation of Th9 development. J Immunol 188(3):968–975

    Article  CAS  PubMed  Google Scholar 

  26. Dardalhon V, Awasthi A, Kwon H, Galileos G, Gao W, Sobel RA, et al. IL-4 inhibits TGF-beta-induced Foxp3+ T cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3(-) effector T cells. Nat Immunol 2008, 9(12): 1347–1355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Fallon PG, Jolin HE, Smith P, Emson CL, Townsend MJ, Fallon R et al (2002) IL-4 induces characteristic Th2 responses even in the combined absence of IL-5, IL-9, and IL-13. Immunity 17(1):7–17

    Article  CAS  PubMed  Google Scholar 

  28. Xue G, Jin G, Fang J, Lu Y (2019) IL-4 together with IL-1beta induces antitumor Th9 cell differentiation in the absence of TGF-beta signaling. Nat Commun 10(1):1376

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Wu B, Huang C, Kato-Maeda M, Hopewell PC, Daley CL, Krensky AM et al (2008) IL-9 is associated with an impaired Th1 immune response in patients with tuberculosis. Clin Immunol 126(2):202–210

    Article  CAS  PubMed  Google Scholar 

  30. Matsuki A, Takatori H, Makita S, Yokota M, Tamachi T, Suto A et al (2017) T-bet inhibits innate lymphoid cell-mediated eosinophilic airway inflammation by suppressing IL-9 production. J Allergy Clin Immunol 139(4):1355–1367. e1356

    Article  CAS  PubMed  Google Scholar 

  31. Smith SE, Hoelzinger DB, Dominguez AL, Van Snick J, Lustgarten J (2011) Signals through 4-1BB inhibit T regulatory cells by blocking IL-9 production enhancing antitumor responses. Cancer Immunol Immunother 60(12):1775–1787

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kaplan MH (2013) Th9 cells: differentiation and disease. Immunol Rev 252(1):104–115

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Jager A, Dardalhon V, Sobel RA, Bettelli E, Kuchroo VK (2009) Th1, Th17, and Th9 effector cells induce experimental autoimmune encephalomyelitis with different pathological phenotypes. J Immunol 183(11):7169–7177

    Article  PubMed  CAS  Google Scholar 

  34. Lu Y, Lin H, Zhai K, Wang X, Zhou Q, Shi H (2016) Interleukin-17 inhibits development of malignant pleural effusion via interleukin-9-dependent mechanism. Sci China Life Sci 59(12):1297–1304

    Article  CAS  PubMed  Google Scholar 

  35. Schutze N, Trojandt S, Kuhn S, Tomm JM, von Bergen M, Simon JC et al (2016) Allergen-induced IL-6 regulates IL-9/IL-17A balance in CD4+ T cells in allergic airway inflammation. J Immunol 197(7):2653–2664

    Article  PubMed  CAS  Google Scholar 

  36. Anuradha R, George PJ, Hanna LE, Chandrasekaran V, Kumaran P, Nutman TB et al (2013) IL-4-, TGF-beta-, and IL-1-dependent expansion of parasite antigen-specific Th9 cells is associated with clinical pathology in human lymphatic filariasis. J Immunol 191(5):2466–2473

    Article  CAS  PubMed  Google Scholar 

  37. Liao W, Spolski R, Li P, Du N, West EE, Ren M et al (2014) Opposing actions of IL-2 and IL-21 on Th9 differentiation correlate with their differential regulation of BCL6 expression. Proc Natl Acad Sci U S A 111(9):3508–3513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Beriou G, Bradshaw EM, Lozano E, Costantino CM, Hastings WD, Orban T et al (2010) TGF-beta induces IL-9 production from human Th17 cells. J Immunol 185(1):46–54

    Article  CAS  PubMed  Google Scholar 

  39. Angkasekwinai P, Sodthawon W, Jeerawattanawart S, Hansakon A, Pattanapanyasat K, Wang YH (2017) ILC2s activated by IL-25 promote antigen-specific Th2 and Th9 functions that contribute to the control of Trichinella spiralis infection. PLoS One 12(9):e0184684

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Verma M, Liu S, Michalec L, Sripada A, Gorska MM, Alam R (2018) Experimental asthma persists in IL-33 receptor knockout mice because of the emergence of thymic stromal lymphopoietin-driven IL-9(+) and IL-13(+) type 2 innate lymphoid cell subpopulations. J Allergy Clin Immunol 142(3):793–803. e798

    Article  CAS  PubMed  Google Scholar 

  41. Pritchard AL, Carroll ML, Burel JG, White OJ, Phipps S, Upham JW (2012) Innate IFNs and plasmacytoid dendritic cells constrain Th2 cytokine responses to rhinovirus: a regulatory mechanism with relevance to asthma. J Immunol 188(12):5898–5905

    Article  CAS  PubMed  Google Scholar 

  42. Siracusa MC, Saenz SA, Hill DA, Kim BS, Headley MB, Doering TA et al (2011) TSLP promotes interleukin-3-independent basophil haematopoiesis and type 2 inflammation. Nature 477(7363):229–233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Murugaiyan G, Beynon V, Pires Da Cunha A, Joller N, Weiner HL (2012) IFN-gamma limits Th9-mediated autoimmune inflammation through dendritic cell modulation of IL-27. J Immunol 189(11):5277–5283

    Article  CAS  PubMed  Google Scholar 

  44. Rivera Vargas T, Cai Z, Shen Y, Dosset M, Benoit-Lizon I, Martin T et al (2017) Selective degradation of PU.1 during autophagy represses the differentiation and antitumour activity of TH9 cells. Nat Commun 8(1):559

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Vegran F, Berger H, Boidot R, Mignot G, Bruchard M, Dosset M et al (2014) The transcription factor IRF1 dictates the IL-21-dependent anticancer functions of TH9 cells. Nat Immunol 15(8):758–766

    Article  CAS  PubMed  Google Scholar 

  46. Maier E, Werner D, Duschl A, Bohle B, Horejs-Hoeck J (2014) Human Th2 but not Th9 cells release IL-31 in a STAT6/NF-kappaB-dependent way. J Immunol 193(2):645–654

    Article  CAS  PubMed  Google Scholar 

  47. Bassil R, Orent W, Olah M, Kurdi AT, Frangieh M, Buttrick T et al (2014) BCL6 controls Th9 cell development by repressing Il9 transcription. J Immunol 193(1):198–207

    Article  CAS  PubMed  Google Scholar 

  48. Elyaman W, Bassil R, Bradshaw EM, Orent W, Lahoud Y, Zhu B et al (2012) Notch receptors and Smad3 signaling cooperate in the induction of interleukin-9-producing T cells. Immunity 36(4):623–634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Nakatsukasa H, Zhang D, Maruyama T, Chen H, Cui K, Ishikawa M et al (2015) The DNA-binding inhibitor Id3 regulates IL-9 production in CD4(+) T cells. Nat Immunol 16(10):1077–1084

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Ye ZJ, Zhou Q, Yin W, Yuan ML, Yang WB, Xiong XZ et al (2012) Differentiation and immune regulation of IL-9-producing CD4+ T cells in malignant pleural effusion. Am J Respir Crit Care Med 186(11):1168–1179

    Article  CAS  PubMed  Google Scholar 

  51. Kelleher K, Bean K, Clark SC, Leung WY, Yang-Feng TL, Chen JW et al (1991) Human interleukin-9: genomic sequence, chromosomal location, and sequences essential for its expression in human T-cell leukemia virus (HTLV)-I-transformed human T cells. Blood 77(7):1436–1441

    Article  CAS  PubMed  Google Scholar 

  52. Lavorgna A, Matsuoka M, Harhaj EW (2014) A critical role for IL-17RB signaling in HTLV-1 tax-induced NF-kappaB activation and T-cell transformation. PLoS Pathog 10(10):e1004418

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Hsieh TH, Hsu CY, Tsai CF, Chiu CC, Liang SS, Wang TN et al (2016) A novel cell-penetrating peptide suppresses breast tumorigenesis by inhibiting beta-catenin/LEF-1 signaling. Sci Rep 6:19156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Zivancevic-Simonovic S, Mihaljevic O, Majstorovic I, Popovic S, Markovic S, Milosevic-Djordjevic O et al (2015) Cytokine production in patients with papillary thyroid cancer and associated autoimmune Hashimoto thyroiditis. Cancer Immunol Immunother 64(8):1011–1019

    Article  CAS  PubMed  Google Scholar 

  55. Hoelzinger DB, Dominguez AL, Cohen PA, Gendler SJ (2014) Inhibition of adaptive immunity by IL9 can be disrupted to achieve rapid T-cell sensitization and rejection of progressive tumor challenges. Cancer Res 74(23):6845–6855

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Qiu L, Lai R, Lin Q, Lau E, Thomazy DM, Calame D et al (2006) Autocrine release of interleukin-9 promotes Jak3-dependent survival of ALK+ anaplastic large-cell lymphoma cells. Blood 108(7):2407–2415

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Koo GC, Tan SY, Tang T, Poon SL, Allen GE, Tan L et al (2012) Janus kinase 3-activating mutations identified in natural killer/T-cell lymphoma. Cancer Discov 2(7):591–597

    Article  CAS  PubMed  Google Scholar 

  58. Lv X, Wang X (2013) The role of interleukin-9 in lymphoma. Leuk Lymphoma 54(7):1367–1372

    Article  CAS  PubMed  Google Scholar 

  59. Kim IK, Kim BS, Koh CH, Seok JW, Park JS, Shin KS et al (2015) Glucocorticoid-induced tumor necrosis factor receptor-related protein co-stimulation facilitates tumor regression by inducing IL-9-producing helper T cells. Nat Med 21(9):1010–1017

    Article  CAS  PubMed  Google Scholar 

  60. Lu Y, Hong S, Li H, Park J, Hong B, Wang L et al (2012) Th9 cells promote antitumor immune responses in vivo. J Clin Invest 122(11):4160–4171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. You FP, Zhang J, Cui T, Zhu R, Lv CQ, Tang HT et al (2017) Th9 cells promote antitumor immunity via IL-9 and IL-21 and demonstrate atypical cytokine expression in breast cancer. Int Immunopharmacol 52:163–167

    Article  CAS  PubMed  Google Scholar 

  62. Lu Y, Wang Q, Yi Q (2014) Anticancer Tc9 cells: long-lived tumor-killing T cells for adoptive therapy. Oncoimmunology 3:e28542

    Article  PubMed  PubMed Central  Google Scholar 

  63. Lu Y, Hong B, Li H, Zheng Y, Zhang M, Wang S et al (2014) Tumor-specific IL-9-producing CD8+ Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers. Proc Natl Acad Sci U S A 111(6):2265–2270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Quezada SA, Peggs KS (2014) An antitumor boost to TH9 cells. Nat Immunol 15(8):703–705

    Article  CAS  PubMed  Google Scholar 

  65. Purwar R, Schlapbach C, Xiao S, Kang HS, Elyaman W, Jiang X et al (2012) Robust tumor immunity to melanoma mediated by interleukin-9-producing T cells. Nat Med 18(8):1248–1253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Shang Y, Kakinuma S, Nishimura M, Kobayashi Y, Nagata K, Shimada Y (2012) Interleukin-9 receptor gene is transcriptionally regulated by nucleolin in T-cell lymphoma cells. Mol Carcinog 51(8):619–627

    Article  CAS  PubMed  Google Scholar 

  67. Li HJ, Sun QM, Liu LZ, Zhang J, Huang J, Wang CH et al (2015) High expression of IL-9R promotes the progression of human hepatocellular carcinoma and indicates a poor clinical outcome. Oncol Rep 34(2):795–802

    Article  CAS  PubMed  Google Scholar 

  68. Eller K, Wolf D, Huber JM, Metz M, Mayer G, McKenzie AN et al (2011) IL-9 production by regulatory T cells recruits mast cells that are essential for regulatory T cell-induced immune suppression. J Immunol 186(1):83–91

    Article  CAS  PubMed  Google Scholar 

  69. Elyaman W, Bradshaw EM, Uyttenhove C, Dardalhon V, Awasthi A, Imitola J et al (2009) IL-9 induces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory T cells. Proc Natl Acad Sci U S A 106(31):12885–12890

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Hoyle GW, Brody AR (2001) IL-9 and lung fibrosis: a Th2 good guy? Am J Respir Cell Mol Biol 24(4):365–367

    Article  CAS  PubMed  Google Scholar 

  71. Liu J, Harberts E, Tammaro A, Girardi N, Filler RB, Fishelevich R et al (2014) IL-9 regulates allergen-specific Th1 responses in allergic contact dermatitis. J Invest Dermatol 134(7):1903–1911

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Fang Y, Chen X, Bai Q, Qin C, Mohamud AO, Zhu Z et al (2015) IL-9 inhibits HTB-72 melanoma cell growth through upregulation of p21 and TRAIL. J Surg Oncol 111(8):969–974

    Article  CAS  PubMed  Google Scholar 

  73. Lendeckel U, Arndt M, Frank K, Spiess A, Reinhold D, Ansorge S (2000) Modulation of WNT-5A expression by actinonin: linkage of APN to the WNT-pathway? Adv Exp Med Biol 477:35–41

    Article  CAS  PubMed  Google Scholar 

  74. Clark RA, Schlapbach C (2017) TH9 cells in skin disorders. Semin Immunopathol 39(1):47–54

    Article  CAS  PubMed  Google Scholar 

  75. Schlapbach C, Gehad A, Yang C, Watanabe R, Guenova E, Teague JE et al (2014) Human TH9 cells are skin-tropic and have autocrine and paracrine proinflammatory capacity. Sci Transl Med 6(219):219ra218

    Article  CAS  Google Scholar 

  76. Kim IK, Chung Y, Kang CY (2016) GITR drives TH9-mediated antitumor immunity. Oncoimmunology 5(5):e1122862

    Article  PubMed  CAS  Google Scholar 

  77. Xiao X, Shi X, Fan Y, Zhang X, Wu M, Lan P et al (2015) GITR subverts Foxp3(+) Tregs to boost Th9 immunity through regulation of histone acetylation. Nat Commun 6:8266

    Article  CAS  PubMed  Google Scholar 

  78. Abdul-Wahid A, Cydzik M, Prodeus A, Alwash M, Stanojcic M, Thompson M et al (2016) Induction of antigen-specific TH 9 immunity accompanied by mast cell activation blocks tumor cell engraftment. Int J Cancer 139(4):841–853

    Article  CAS  PubMed  Google Scholar 

  79. Vegran F, Apetoh L, Ghiringhelli F (2015) Th9 cells: a novel CD4 T-cell subset in the immune war against cancer. Cancer Res 75(3):475–479

    Article  CAS  PubMed  Google Scholar 

  80. Lu LF, Lind EF, Gondek DC, Bennett KA, Gleeson MW, Pino-Lagos K et al (2006) Mast cells are essential intermediaries in regulatory T-cell tolerance. Nature 442(7106):997–1002

    Article  CAS  PubMed  Google Scholar 

  81. Park J, Li H, Zhang M, Lu Y, Hong B, Zheng Y et al (2014) Murine Th9 cells promote the survival of myeloid dendritic cells in cancer immunotherapy. Cancer Immunol Immunother 63(8):835–845

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Jiang Y, Chen J, Bi E, Zhao Y, Qin T, Wang Y et al (2019) TNF-alpha enhances Th9 cell differentiation and antitumor immunity via TNFR2-dependent pathways. J Immunother Cancer 7(1):28

    Article  PubMed  PubMed Central  Google Scholar 

  83. Ma X, Bi E, Huang C, Lu Y, Xue G, Guo X et al (2018) Cholesterol negatively regulates IL-9-producing CD8(+) T cell differentiation and antitumor activity. J Exp Med 215(6):1555–1569

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Petrella TM, Tozer R, Belanger K, Savage KJ, Wong R, Smylie M et al (2012) Interleukin-21 has activity in patients with metastatic melanoma: a phase II study. J Clin Oncol Off J Am Soc Clin Oncol 30(27):3396–3401

    Article  CAS  Google Scholar 

  85. Zeng R, Spolski R, Finkelstein SE, Oh S, Kovanen PE, Hinrichs CS et al (2005) Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function. J Exp Med 201(1):139–148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Strengell M, Matikainen S, Siren J, Lehtonen A, Foster D, Julkunen I et al (2003) IL-21 in synergy with IL-15 or IL-18 enhances IFN-gamma production in human NK and T cells. J Immunol 170(11):5464–5469

    Article  CAS  PubMed  Google Scholar 

  87. Kasaian MT, Whitters MJ, Carter LL, Lowe LD, Jussif JM, Deng B et al (2002) IL-21 limits NK cell responses and promotes antigen-specific T cell activation: a mediator of the transition from innate to adaptive immunity. Immunity 16(4):559–569

    Article  CAS  PubMed  Google Scholar 

  88. Chen N, Lv X, Li P, Lu K, Wang X (2014) Role of high expression of IL-9 in prognosis of CLL. Int J Clin Exp Pathol 7(2):716–721

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Yang Z, Zhang B, Li D, Lv M, Huang C, Shen GX et al (2010) Mast cells mobilize myeloid-derived suppressor cells and Treg cells in tumor microenvironment via IL-17 pathway in murine hepatocarcinoma model. PLoS One 5(1):e8922

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Rawstron AC, Bottcher S, Letestu R, Villamor N, Fazi C, Kartsios H et al (2013) Improving efficiency and sensitivity: European Research Initiative in CLL (ERIC) update on the international harmonised approach for flow cytometric residual disease monitoring in CLL. Leukemia 27(1):142–149

    Article  CAS  PubMed  Google Scholar 

  91. Nagato T, Kobayashi H, Kishibe K, Takahara M, Ogino T, Ishii H et al (2005) Expression of interleukin-9 in nasal natural killer/T-cell lymphoma cell lines and patients. Clin Cancer Res 11(23):8250–8257

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors’ research is supported by grants from the National Natural Science Foundation for Key Programs of China (31730024, G.L.) and National Natural Science Foundation for General Programs of China (31671524 and 81273201, G.L.).

Competing Financial Interests

The authors declare no competing financial interests.

Author information

Authors and Affiliations

  1. Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing, China

    Ying He, Lin Dong, Yejin Cao & Guangwei Liu

  2. State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China

    Yujing Bi

Authors
  1. Ying He
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lin Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yejin Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yujing Bi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Guangwei Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Guangwei Liu .

Editor information

Editors and Affiliations

  1. Department of Radiology, Columbia University Medical Center, New York, NY, USA, Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil

    Alexander Birbrair

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

He, Y., Dong, L., Cao, Y., Bi, Y., Liu, G. (2020). IL-9 and Th9 Cells in Tumor Immunity. In: Birbrair, A. (eds) Tumor Microenvironment. Advances in Experimental Medicine and Biology, vol 1240. Springer, Cham. https://doi.org/10.1007/978-3-030-38315-2_3

Download citation

Publish with us

Policies and ethics

Search

Navigation