Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Seminars in Immunopathology
Published in: Seminars in Immunopathology 1/2017

Open Access 01-01-2017 | Review

TH9 cells in anti-tumor immunity

Authors: Thaiz Rivera Vargas, Etienne Humblin, Frédérique Végran, François Ghiringhelli, Lionel Apetoh

Published in: Seminars in Immunopathology | Issue 1/2017

Login to get access

Abstract

IL-9 was initially identified as a T cell growth factor with a potential oncogenic activity. Accordingly, IL-9 drives tumor growth in most hematological cancers. However, the links between IL-9 and cancer progression have been recently revisited following the discovery of TH9 cells. TH9 cells, which have been characterized in 2008 as a proinflammatory CD4 T cell subset that promotes protection against parasites and drives tissue inflammation in colitis, actually harbor potent IL-9-dependent anti-cancer properties in solid tumors and especially melanoma. While the molecular mechanisms underlying these observations are still being investigated, TH9 cells were demonstrated to activate both innate and adaptive immune responses, thereby favoring anti-cancer immunity and tumor elimination. Human TH9 cells have also been identified in cancer tissues, but their functions remain elusive. The present review aims to discuss the anti-cancer potential of TH9 cells and their possible clinical relevance for cancer immunotherapy.
Literature
1.
W.B. Coley, (1991) The treatment of malignant tumors by repeated inoculations of erysipelas. With a report of ten original cases. 1893, Clin Orthop Relat Res (262) 3–11.
2.
3.
Pages F, Galon J, Dieu-Nosjean MC, Tartour E, Sautes-Fridman C, Fridman WH (2010) Immune infiltration in human tumors: a prognostic factor that should not be ignored. Oncogene 29(8):1093–1102CrossRefPubMed
4.
Kennedy R, Celis E (2008) Multiple roles for CD4+ T cells in anti-tumor immune responses. Immunol Rev 222:129–144CrossRefPubMed
5.
6.
Burkholder B, Huang RY, Burgess R, Luo S, Jones VS, Zhang W, Lv ZQ, Gao CY, Wang BL, Zhang YM, Huang RP (2014) Tumor-induced perturbations of cytokines and immune cell networks. Biochim Biophys Acta 1845(2):182–201PubMed
7.
Li Z, Jiang J, Wang Z, Zhang J, Xiao M, Wang C, Lu Y, Qin Z (2008) Endogenous interleukin-4 promotes tumor development by increasing tumor cell resistance to apoptosis. Cancer Res 68(21):8687–8694CrossRefPubMed
8.
Terabe M, Park JM, Berzofsky JA (2004) Role of IL-13 in regulation of anti-tumor immunity and tumor growth. Cancer Immunol Immunother 53(2):79–85CrossRefPubMed
9.
10.
11.
12.
Wang L, Yi T, Kortylewski M, Pardoll DM, Zeng D, Yu H (2009) IL-17 can promote tumor growth through an IL-6-Stat3 signaling pathway. J Exp Med 206(7):1457–1464CrossRefPubMedPubMedCentral
13.
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(2):362–373CrossRefPubMedPubMedCentral
14.
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(5):787–798CrossRefPubMedPubMedCentral
15.
Veldhoen M, Uyttenhove C, van Snick J, Helmby H, Westendorf A, Buer J, Martin B, Wilhelm C, Stockinger B (2008) Transforming growth factor-beta ‘reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat Immunol 9(12):1341–1346CrossRefPubMed
16.
Dardalhon V, Awasthi A, Kwon H, Galileos G, Gao W, Sobel RA, Mitsdoerffer M, Strom TB, Elyaman W, Ho IC, Khoury S, Oukka M, Kuchroo VK (2008) 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 9(12):1347–1355CrossRefPubMedPubMedCentral
17.
Renauld JC, van der Lugt N, Vink A, van Roon M, Godfraind C, Warnier G, Merz H, Feller A, Berns A, Van Snick J (1994) Thymic lymphomas in interleukin 9 transgenic mice. Oncogene 9(5):1327–1332PubMed
18.
Uyttenhove C, Simpson RJ, Van Snick J (1988) Functional and structural characterization of P40, a mouse glycoprotein with T-cell growth factor activity. Proc Natl Acad Sci U S A 85(18):6934–6938CrossRefPubMedPubMedCentral
19.
Fischer M, Bijman M, Molin D, Cormont F, Uyttenhove C, van Snick J, Sundstrom C, Enblad G, Nilsson G (2003) Increased serum levels of interleukin-9 correlate to negative prognostic factors in Hodgkin’s lymphoma. Leukemia 17(12):2513–2516CrossRefPubMed
20.
Elyaman W, Bradshaw EM, Uyttenhove C, Dardalhon V, Awasthi A, Imitola J, Bettelli E, Oukka M, van Snick J, Renauld JC, Kuchroo VK, Khoury SJ (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):12885–12890CrossRefPubMedPubMedCentral
21.
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):6845–6855CrossRefPubMedPubMedCentral
22.
Purwar R, Schlapbach C, Xiao S, Kang HS, Elyaman W, Jiang X, Jetten AM, Khoury SJ, Fuhlbrigge RC, Kuchroo VK, Clark RA, Kupper TS (2012) Robust tumor immunity to melanoma mediated by interleukin-9-producing T cells. Nat Med 18(8):1248–1253CrossRefPubMedPubMedCentral
23.
Nakatsukasa H, Zhang D, Maruyama T, Chen H, Cui K, Ishikawa M, Deng L, Zanvit P, Tu E, Jin W, Abbatiello B, Goldberg N, Chen Q, Sun L, Zhao K, Chen W (2015) The DNA-binding inhibitor Id3 regulates IL-9 production in CD4(+) T cells. Nat Immunol 16(10):1077–1084CrossRefPubMed
24.
Eller K, Wolf D, Huber JM, Metz M, Mayer G, McKenzie AN, Maurer M, Rosenkranz AR, Wolf AM (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):83–91CrossRefPubMed
25.
Grimbaldeston MA, Chen CC, Piliponsky AM, Tsai M, Tam SY, Galli SJ (2005) Mast cell-deficient W-sash c-kit mutant kit W-sh/W-sh mice as a model for investigating mast cell biology in vivo. Am J Pathol 167(3):835–848CrossRefPubMedPubMedCentral
26.
Abdul-Wahid A, Cydzik M, Prodeus A, Alwash M, Stanojcic M, Thompson M, Huang EH, Shively JE, Gray-Owen SD, Gariepy J (2016) Induction of antigen-specific TH 9 immunity accompanied by mast cell activation blocks tumor cell engraftment. Int J Cancer 139(4):841–853CrossRefPubMed
27.
Lu Y, Hong S, Li H, Park J, Hong B, Wang L, Zheng Y, Liu Z, Xu J, He J, Yang J, Qian J, Yi Q (2012) Th9 cells promote antitumor immune responses in vivo. J Clin Invest 122(11):4160–4171CrossRefPubMedPubMedCentral
28.
Zhao Y, Chu X, Chen J, Wang Y, Gao S, Jiang Y, Zhu X, Tan G, Zhao W, Yi H, Xu H, Ma X, Lu Y, Yi Q, Wang S (2016) Dectin-1-activated dendritic cells trigger potent antitumour immunity through the induction of Th9 cells. Nat Commun 7:12368CrossRefPubMedPubMedCentral
29.
Vegran F, Berger H, Boidot R, Mignot G, Bruchard M, Dosset M, Chalmin F, Rebe C, Derangere V, Ryffel B, Kato M, Prevost-Blondel A, Ghiringhelli F, Apetoh L (2014) The transcription factor IRF1 dictates the IL-21-dependent anticancer functions of TH9 cells. Nat Immunol 15(8):758–766CrossRefPubMed
30.
Park J, Li H, Zhang M, Lu Y, Hong B, Zheng Y, He J, Yang J, Qian J, Yi Q (2014) Murine Th9 cells promote the survival of myeloid dendritic cells in cancer immunotherapy. Cancer Immunol Immunother 63(8):835–845CrossRefPubMedPubMedCentral
31.
Kim IK, Kim BS, Koh CH, Seok JW, Park JS, Shin KS, Bae EA, Lee GE, Jeon H, Cho J, Jung Y, Han D, Kwon BS, Lee HY, Chung Y, Kang CY (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):1010–1017CrossRefPubMed
32.
Xiao X, Shi X, Fan Y, Zhang X, Wu M, Lan P, Minze L, Fu YX, Ghobrial RM, Liu W, Li XC (2015) GITR subverts Foxp3(+) Tregs to boost Th9 immunity through regulation of histone acetylation. Nat Commun 6:8266CrossRefPubMedPubMedCentral
33.
B.P. Miao, R.S. Zhang, H.J. Sun, Y.P. Yu, T. Chen, L.J. Li, J.Q. Liu, J. Liu, H.Q. Yu, M. Zhang, Z.G. Liu, P.C. Yang, (2015) Inhibition of squamous cancer growth in a mouse model by Staphylococcal enterotoxin B-triggered Th9 cell expansion, Cell Mol Immunol.
34.
Fang Y, Chen X, Bai Q, Qin C, Mohamud AO, Zhu Z, Ball TW, Ruth CM, Newcomer DR, Herrick EJ, Nicholl MB (2015) IL-9 inhibits HTB-72 melanoma cell growth through upregulation of p21 and TRAIL. J Surg Oncol 111(8):969–974CrossRefPubMed
35.
Wilhelm C, Hirota K, Stieglitz B, Van Snick J, Tolaini M, Lahl K, Sparwasser T, Helmby H, Stockinger B (2011) An IL-9 fate reporter demonstrates the induction of an innate IL-9 response in lung inflammation. Nat Immunol 12(11):1071–1077CrossRefPubMedPubMedCentral
36.
Tan C, Aziz MK, Lovaas JD, Vistica BP, Shi G, Wawrousek EF, Gery I (2010) Antigen-specific Th9 cells exhibit uniqueness in their kinetics of cytokine production and short retention at the inflammatory site. J Immunol 185(11):6795–6801CrossRefPubMedPubMedCentral
37.
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):7169–7177CrossRefPubMedPubMedCentral
38.
Schmitt E, Germann T, Goedert S, Hoehn P, Huels C, Koelsch S, Kuhn R, Muller W, Palm N, Rude E (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):3989–3996PubMed
39.
Tofukuji S, Kuwahara M, Suzuki J, Ohara O, Nakayama T, Yamashita M (2012) Identification of a new pathway for Th1 cell development induced by cooperative stimulation with IL-4 and TGF-beta. J Immunol 188(10):4846–4857CrossRefPubMed
40.
Schlapbach C, Gehad A, Yang C, Watanabe R, Guenova E, Teague JE, Campbell L, Yawalkar N, Kupper TS, Clark RA (2014) Human TH9 cells are skin-tropic and have autocrine and paracrine proinflammatory capacity. Sci Transl Med 6(219):219ra8CrossRefPubMedPubMedCentral
41.
Gu ZW, Wang YX, Cao ZW (2015) T-helper type 9 cells play a central role in the pathogenesis of respiratory epithelial adenomatoid hamartoma. Medicine (Baltimore) 94(26):e1050CrossRef
42.
Ye ZJ, Zhou Q, Yin W, Yuan ML, Yang WB, Xiong XZ, Zhang JC, Shi HZ (2012) Differentiation and immune regulation of IL-9-producing CD4+ T cells in malignant pleural effusion. Am J Respir Crit Care Med 186(11):1168–1179CrossRefPubMed
43.
Bu XN, Zhou Q, Zhang JC, Ye ZJ, Tong ZH, Shi HZ (2013) Recruitment and phenotypic characteristics of interleukin 9-producing CD4+ T cells in malignant pleural effusion. Lung 191(4):385–389CrossRefPubMed
44.
Parrot T, Allard M, Oger R, Benlalam H, Raingeard de la Bletiere D, Coutolleau A, Preisser L, Desfrancois J, Khammari A, Dreno B, Labarriere N, Delneste Y, Guardiola P, Gervois N (2016) IL-9 promotes the survival and function of human melanoma-infiltrating CD4(+) CD8(+) double-positive T cells. Eur J Immunol 46(7):1770–1782CrossRefPubMed
45.
Yang XR, Pfeiffer RM, Wheeler W, Yeager M, Chanock S, Tucker MA, Goldstein AM (2009) Identification of modifier genes for cutaneous malignant melanoma in melanoma-prone families with and without CDKN2A mutations. Int J Cancer 125(12):2912–2917CrossRefPubMedPubMedCentral
46.
47.
Rosenberg SA, Restifo NP (2015) Adoptive cell transfer as personalized immunotherapy for human cancer. Science 348(6230):62–68CrossRefPubMed
48.
Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, Jungbluth A, Gnjatic S, Thompson JA, Yee C (2008) Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med 358(25):2698–2703CrossRefPubMedPubMedCentral
49.
Apetoh L, Ladoire S, Coukos G, Ghiringhelli F (2015) Combining immunotherapy and anticancer agents: the right path to achieve cancer cure? Ann Oncol 26(9):1813–1823CrossRefPubMed
Metadata
Title
TH9 cells in anti-tumor immunity
Authors
Thaiz Rivera Vargas
Etienne Humblin
Frédérique Végran
François Ghiringhelli
Lionel Apetoh
Publication date
01-01-2017
Publisher
Springer Berlin Heidelberg
Published in
Seminars in Immunopathology / Issue 1/2017
Print ISSN: 1863-2297
Electronic ISSN: 1863-2300
DOI
https://doi.org/10.1007/s00281-016-0599-4

Other articles of this Issue 1/2017

Seminars in Immunopathology 1/2017 Go to the issue

Review

TNF superfamily cytokines in the promotion of Th9 differentiation and immunopathology

Review

Th9 cells in inflammatory bowel diseases

Review

Discovery and initial characterization of Th9 cells: the early years

Review

IL-9 and Th9 in parasite immunity

Review

Th9 cells in the pathogenesis of EAE and multiple sclerosis

Review

The transcription factor network in Th9 cells

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24 to hear Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits