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
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Molecular Cancer
Published in: Molecular Cancer 1/2016

Open Access 01-12-2016 | Review

Emerging roles of T helper 17 and regulatory T cells in lung cancer progression and metastasis

Authors: Erin A. Marshall, Kevin W. Ng, Sonia H. Y. Kung, Emma M. Conway, Victor D. Martinez, Elizabeth C. Halvorsen, David A. Rowbotham, Emily A. Vucic, Adam W. Plumb, Daiana D. Becker-Santos, Katey S. S. Enfield, Jennifer Y. Kennett, Kevin L. Bennewith, William W. Lockwood, Stephen Lam, John C. English, Ninan Abraham, Wan L. Lam

Published in: Molecular Cancer | Issue 1/2016

Login to get access

Abstract

Lung cancer is a leading cause of cancer-related deaths worldwide. Lung cancer risk factors, including smoking and exposure to environmental carcinogens, have been linked to chronic inflammation. An integral feature of inflammation is the activation, expansion and infiltration of diverse immune cell types, including CD4+ T cells. Within this T cell subset are immunosuppressive regulatory T (Treg) cells and pro-inflammatory T helper 17 (Th17) cells that act in a fine balance to regulate appropriate adaptive immune responses.
In the context of lung cancer, evidence suggests that Tregs promote metastasis and metastatic tumor foci development. Additionally, Th17 cells have been shown to be an integral component of the inflammatory milieu in the tumor microenvironment, and potentially involved in promoting distinct lung tumor phenotypes. Studies have shown that the composition of Tregs and Th17 cells are altered in the tumor microenvironment, and that these two CD4+ T cell subsets play active roles in promoting lung cancer progression and metastasis.
We review current knowledge on the influence of Treg and Th17 cells on lung cancer tumorigenesis, progression, metastasis and prognosis. Furthermore, we discuss the potential biological and clinical implications of the balance among Treg/Th17 cells in the context of the lung tumor microenvironment and highlight the potential prognostic function and relationship to metastasis in lung cancer.
Literature
1.
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.PubMedCrossRef
2.
3.
Pikor LA, Ramnarine VR, Lam S, Lam WL. Genetic alterations defining NSCLC subtypes and their therapeutic implications. Lung Cancer. 2013;82(2):179–89.PubMedCrossRef
4.
Kim CF, Jackson EL, Woolfenden AE, Lawrence S, Babar I, Vogel S, Crowley D, Bronson RT, Jacks T. Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell. 2005;121(6):823–35.PubMedCrossRef
5.
Howlader N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA, editors. SEER Cancer Statistics Review, 1975–2012. Bethesda: National Cancer Institute; 2015. http://​seer.​cancer.​gov/​csr/​1975_​2012/​, based on November 2014 SEER data submission, posted to the SEER web site.
6.
Sun S, Schiller JH, Gazdar AF. Lung cancer in never smokers--a different disease. Nat Rev Cancer. 2007;7(10):778–90.PubMedCrossRef
7.
8.
Park KS, Liang MC, Raiser DM, Zamponi R, Roach RR, Curtis SJ, Walton Z, Schaffer BE, Roake CM, Zmoos AF, et al. Characterization of the cell of origin for small cell lung cancer. Cell Cycle. 2011;10(16):2806–15.PubMedPubMedCentralCrossRef
9.
10.
11.
Gomes M, Teixeira AL, Coelho A, Araujo A, Medeiros R. The role of inflammation in lung cancer. Adv Exp Med Biol. 2014;816:1–23.PubMedCrossRef
12.
Sato M, Shames DS, Gazdar AF, Minna JD. A translational view of the molecular pathogenesis of lung cancer. J Thorac Oncol. 2007;2(4):327–43.PubMedCrossRef
13.
Hajdu SI. Much overlooked causes of lung cancer. Ann Clin Lab Sci. 2011;41(1):97–101.PubMed
14.
Martinez VD, Vucic EA, Lam S, Lam WL. Arsenic and lung cancer in never-smokers: lessons from Chile. Am J Respir Crit Care Med. 2012;185(10):1131–2.PubMedCrossRef
15.
Hubaux R, Becker-Santos DD, Enfield KS, Lam S, Lam WL, Martinez VD. Arsenic, asbestos and radon: emerging players in lung tumorigenesis. Environ Health. 2012;11:89.PubMedPubMedCentralCrossRef
16.
Hubaux R, Becker-Santos DD, Enfield KS, Rowbotham D, Lam S, Lam WL, Martinez VD. Molecular features in arsenic-induced lung tumors. Mol Cancer. 2013;12:20.PubMedPubMedCentralCrossRef
17.
18.
Shiels MS, Katki HA, Freedman ND, Purdue MP, Wentzensen N, Trabert B, Kitahara CM, Furr M, Li Y, Kemp TJ, et al. Cigarette smoking and variations in systemic immune and inflammation markers. J Natl Cancer Inst. 2014;106(11):dju294.PubMedPubMedCentralCrossRef
19.
Shiels MS, Pfeiffer RM, Hildesheim A, Engels EA, Kemp TJ, Park JH, Katki HA, Koshiol J, Shelton G, Caporaso NE, et al. Circulating inflammation markers and prospective risk for lung cancer. J Natl Cancer Inst. 2013;105(24):1871–80.PubMedPubMedCentralCrossRef
20.
Wang GZ, Cheng X, Li XC, Liu YQ, Wang XQ, Shi X, Wang ZY, Guo YQ, Wen ZS, Huang YC, et al. Tobacco smoke induces production of chemokine CCL20 to promote lung cancer. Cancer Lett. 2015;363(1):60–70.PubMedCrossRef
21.
Sin DD, Man SF, McWilliams A, Lam S. Surfactant protein D and bronchial dysplasia in smokers at high risk of lung cancer. Chest. 2008;134(3):582–8.PubMedCrossRef
22.
Filaire E, Dupuis C, Galvaing G, Aubreton S, Laurent H, Richard R, Filaire M. Lung cancer: what are the links with oxidative stress, physical activity and nutrition. Lung Cancer. 2013;82(3):383–9.PubMedCrossRef
23.
Rahman I. Pharmacological antioxidant strategies as therapeutic interventions for COPD. Biochim Biophys Acta. 2012;1822(5):714–28.PubMedCrossRef
24.
Regan EA, Mazur W, Meoni E, Toljamo T, Millar J, Vuopala K, Bowler RP, Rahman I, Nicks ME, Crapo JD, et al. Smoking and COPD increase sputum levels of extracellular superoxide dismutase. Free Radic Biol Med. 2011;51(3):726–32.PubMedCrossRef
25.
Xu A, Huang X, Lien YC, Bao L, Yu Z, Hei TK. Genotoxic mechanisms of asbestos fibers: role of extranuclear targets. Chem Res Toxicol. 2007;20(5):724–33.PubMedCrossRef
26.
Heintz NH, Janssen-Heininger YM, Mossman BT. Asbestos, lung cancers, and mesotheliomas: from molecular approaches to targeting tumor survival pathways. Am J Respir Cell Mol Biol. 2010;42(2):133–9.PubMedPubMedCentralCrossRef
27.
28.
Ferro A, Zebedeo CN, Davis C, Ng KW, Pfau JC. Amphibole, but not chrysotile, asbestos induces anti-nuclear autoantibodies and IL-17 in C57BL/6 mice. J Immunotoxicol. 2014;11(3):283–90.PubMedCrossRef
29.
Zebedeo CN, Davis C, Pena C, Ng KW, Pfau JC. Erionite induces production of autoantibodies and IL-17 in C57BL/6 mice. Toxicol Appl Pharmacol. 2014;275(3):257–64.PubMedPubMedCentralCrossRef
30.
El-Zein RA, Young RP, Hopkins RJ, Etzel CJ. Genetic predisposition to chronic obstructive pulmonary disease and/or lung cancer: important considerations when evaluating risk. Cancer Prev Res (Phila). 2012;5(4):522–7.CrossRef
31.
Vermaelen K, Brusselle G. Exposing a deadly alliance: novel insights into the biological links between COPD and lung cancer. Pulm Pharmacol Ther. 2013;26(5):544–54.PubMedCrossRef
32.
33.
Sekine Y, Hata A, Koh E, Hiroshima K. Lung carcinogenesis from chronic obstructive pulmonary disease: characteristics of lung cancer from COPD and contribution of signal transducers and lung stem cells in the inflammatory microenvironment. Gen Thorac Cardiovasc Surg. 2014;62(7):415–21.PubMedCrossRef
34.
de Visser KE, Eichten A, Coussens LM. Paradoxical roles of the immune system during cancer development. Nat Rev Cancer. 2006;6(1):24–37.PubMedCrossRef
35.
36.
37.
Conway EM, Pikor LA, Kung SH, Hamilton MJ, Lam S, Lam WL, Bennewith KL. Macrophages, Inflammation, and Lung Cancer. Am J Respir Crit Care Med. 2016;193(2):116–30.PubMedCrossRef
38.
39.
40.
Brandau S, Dumitru CA, Lang S. Protumor and antitumor functions of neutrophil granulocytes. Semin Immunopathol. 2013;35(2):163–76.PubMedCrossRef
41.
Bruno A, Ferlazzo G, Albini A, Noonan DM. A think tank of TINK/TANKs: tumor-infiltrating/tumor-associated natural killer cells in tumor progression and angiogenesis. J Natl Cancer Inst. 2014;106(8):dju200.PubMedPubMedCentralCrossRef
42.
Nelson BH. CD20+ B cells: the other tumor-infiltrating lymphocytes. J Immunol. 2010;185(9):4977–82.PubMedCrossRef
43.
Balkwill F, Montfort A, Capasso M. B regulatory cells in cancer. Trends Immunol. 2013;34(4):169–73.PubMedCrossRef
44.
Kim HJ, Cantor H. CD4 T-cell subsets and tumor immunity: the helpful and the not-so-helpful. Cancer Immunol Res. 2014;2(2):91–8.PubMedCrossRef
45.
Li K, Zhang Q, Zhang Y, Yang J, Zheng J. T-cell-associated cellular immunotherapy for lung cancer. J Cancer Res Clin Oncol. 2015;141(7):1249–58.PubMedCrossRef
46.
Lakshmi Narendra B, Eshvendar Reddy K, Shantikumar S, Ramakrishna S. Immune system: a double-edged sword in cancer. Inflamm Res. 2013;62(9):823–34.PubMedCrossRef
47.
Eisenstein EM, Williams CB. The T(reg)/Th17 cell balance: a new paradigm for autoimmunity. Pediatr Res. 2009;65(5 Pt 2):26R–31R.PubMedCrossRef
48.
Zhou L, Lopes JE, Chong MM, Ivanov II, Min R, Victora GD, Shen Y, Du J, Rubtsov YP, Rudensky AY, et al. TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature. 2008;453(7192):236–40.PubMedPubMedCentralCrossRef
49.
Du J, Huang C, Zhou B, Ziegler SF. Isoform-specific inhibition of ROR alpha-mediated transcriptional activation by human FOXP3. J Immunol. 2008;180(7):4785–92.PubMedCrossRef
50.
51.
Lee HM, Bautista JL, Hsieh CS. Thymic and peripheral differentiation of regulatory T cells. Adv Immunol. 2011;112:25–71.PubMedCrossRef
52.
Halvorsen EC, Mahmoud SM, Bennewith KL. Emerging roles of regulatory T cells in tumour progression and metastasis. Cancer Metastasis Rev. 2014;33(4):1025–41.PubMedCrossRef
53.
Geis AL, Fan H, Wu X, Wu S, Huso DL, Wolfe JL, Sears CL, Pardoll DM, Housseau F. Regulatory T-cell Response to Enterotoxigenic Bacteroides fragilis Colonization Triggers IL17-Dependent Colon Carcinogenesis. Cancer Discov. 2015;5(10):1098–109.PubMedPubMedCentralCrossRef
54.
55.
56.
Savage PA, Malchow S, Leventhal DS. Basic principles of tumor-associated regulatory T cell biology. Trends Immunol. 2013;34(1):33–40.PubMedCrossRef
57.
d'Hennezel E, Piccirillo CA. Analysis of human FOXP3+ Treg cells phenotype and function. Methods Mol Biol. 2011;707:199–218.PubMedCrossRef
58.
Francisco LM, Salinas VH, Brown KE, Vanguri VK, Freeman GJ, Kuchroo VK, Sharpe AH. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med. 2009;206(13):3015–29.PubMedPubMedCentralCrossRef
59.
60.
Okazaki T, Chikuma S, Iwai Y, Fagarasan S, Honjo T. A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application. Nat Immunol. 2013;14(12):1212–8.PubMedCrossRef
61.
He J, Hu Y, Hu M, Li B. Development of PD-1/PD-L1 Pathway in Tumor Immune Microenvironment and Treatment for Non-Small Cell Lung Cancer. Sci Rep. 2015;5:13110.PubMedPubMedCentralCrossRef
62.
Takenaka MC, Robson S, Quintana FJ. Regulation of the T Cell Response by CD39. Trends Immunol. 2016;37(7):427–39.PubMedCrossRef
63.
Vinay DS, Ryan EP, Pawelec G, Talib WH, Stagg J, Elkord E, Lichtor T, Decker WK, Whelan RL, Kumara HM, et al. Immune evasion in cancer: Mechanistic basis and therapeutic strategies. Semin Cancer Biol. 2015;35(Suppl):S185–98.PubMedCrossRef
64.
Domagala-Kulawik J, Osinska I, Hoser G. Mechanisms of immune response regulation in lung cancer. Translational Lung Cancer Res. 2014;3(1):15–22.
65.
Granville CA, Memmott RM, Balogh A, Mariotti J, Kawabata S, Han W, Lopiccolo J, Foley J, Liewehr DJ, Steinberg SM, et al. A central role for Foxp3+ regulatory T cells in K-Ras-driven lung tumorigenesis. PLoS One. 2009;4(3):e5061.PubMedPubMedCentralCrossRef
66.
Ganesan AP, Johansson M, Ruffell B, Yagui-Beltran A, Lau J, Jablons DM, Coussens LM. Tumor-infiltrating regulatory T cells inhibit endogenous cytotoxic T cell responses to lung adenocarcinoma. J Immunol. 2013;191(4):2009–17.PubMedPubMedCentralCrossRef
67.
Wang W, Hodkinson P, McLaren F, MacKinnon A, Wallace W, Howie S, Sethi T. Small cell lung cancer tumour cells induce regulatory T lymphocytes, and patient survival correlates negatively with FOXP3+ cells in tumour infiltrate. Int J Cancer. 2012;131(6):E928–37.PubMedCrossRef
68.
Shimizu K, Nakata M, Hirami Y, Yukawa T, Maeda A, Tanemoto K. Tumor-infiltrating Foxp3+ regulatory T cells are correlated with cyclooxygenase-2 expression and are associated with recurrence in resected non-small cell lung cancer. J Thorac Oncol. 2010;5(5):585–90.PubMedCrossRef
69.
Razani-Boroujerdi S, Sopori ML. Early manifestations of NNK-induced lung cancer: role of lung immunity in tumor susceptibility. Am J Respir Cell Mol Biol. 2007;36(1):13–9.PubMedCrossRef
70.
Erfani N, Mehrabadi SM, Ghayumi MA, Haghshenas MR, Mojtahedi Z, Ghaderi A, Amani D. Increase of regulatory T cells in metastatic stage and CTLA-4 over expression in lymphocytes of patients with non-small cell lung cancer (NSCLC). Lung Cancer. 2012;77(2):306–11.PubMedCrossRef
71.
Schneider T, Kimpfler S, Warth A, Schnabel PA, Dienemann H, Schadendorf D, Hoffmann H, Umansky V. Foxp3(+) regulatory T cells and natural killer cells distinctly infiltrate primary tumors and draining lymph nodes in pulmonary adenocarcinoma. J Thorac Oncol. 2011;6(3):432–8.PubMedCrossRef
72.
Black CC, Turk MJ, Dragnev K, Rigas JR. Adenocarcinoma contains more immune tolerance regulatory t-cell lymphocytes (versus squamous carcinoma) in non-small-cell lung cancer. Lung. 2013;191(3):265–70.PubMedCrossRef
73.
Smyth MJ, Teng MW, Swann J, Kyparissoudis K, Godfrey DI, Hayakawa Y. CD4 + CD25+ T regulatory cells suppress NK cell-mediated immunotherapy of cancer. J Immunol. 2006;176(3):1582–7.PubMedCrossRef
74.
Petersen RP, Campa MJ, Sperlazza J, Conlon D, Joshi MB, Harpole Jr DH, Patz Jr EF. Tumor infiltrating Foxp3+ regulatory T-cells are associated with recurrence in pathologic stage I NSCLC patients. Cancer. 2006;107(12):2866–72.PubMedCrossRef
75.
Koyama K, Kagamu H, Miura S, Hiura T, Miyabayashi T, Itoh R, Kuriyama H, Tanaka H, Tanaka J, Yoshizawa H, et al. Reciprocal CD4+ T-cell balance of effector CD62Llow CD4+ and CD62LhighCD25+ CD4+ regulatory T cells in small cell lung cancer reflects disease stage. Clin Cancer Res. 2008;14(21):6770–9.PubMedCrossRef
76.
Reck M, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, Sebastian M, Lu H, Cuillerot JM, Lynch TJ. Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial. Ann Oncol. 2013;24(1):75–83.PubMedCrossRef
77.
Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, Sebastian M, Neal J, Lu H, Cuillerot JM, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol Off J Am Soc Clin Oncol. 2012;30(17):2046–54.CrossRef
78.
Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med. 2015;373(2):123–35.PubMedPubMedCentralCrossRef
79.
Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 2015;373(17):1627–39.PubMedCrossRef
80.
Guibert N, Mazieres J. Nivolumab for treating non-small cell lung cancer. Expert Opin Biol Ther. 2015;15(12):1789–97.PubMedCrossRef
81.
82.
Wang A, Wang Z, Cao Y, Cheng S, Chen H, Bunjhoo H, Xie J, Wang C, Xu Y, Xiong W. CCL2/CCR2-dependent recruitment of Th17 cells but not Tc17 cells to the lung in a murine asthma model. Int Arch Allergy Immunol. 2015;166(1):52–62.PubMedCrossRef
83.
Glosson-Byers NL, Sehra S, Stritesky GL, Yu Q, Awe O, Pham D, Bruns HA, Kaplan MH. Th17 cells demonstrate stable cytokine production in a proallergic environment. J Immunol. 2014;193(6):2631–40.PubMedPubMedCentralCrossRef
84.
Pham D, Sehra S, Sun X, Kaplan MH. The transcription factor Etv5 controls TH17 cell development and allergic airway inflammation. J Allergy Clin Immunol. 2014;134(1):204–14.PubMedPubMedCentralCrossRef
85.
Tsai HC, Velichko S, Hung LY, Wu R. IL-17A and Th17 cells in lung inflammation: an update on the role of Th17 cell differentiation and IL-17R signaling in host defense against infection. Clin Dev Immunol. 2013;2013:267971.PubMedPubMedCentralCrossRef
86.
Song L, Weng D, Dai W, Tang W, Chen S, Li C, Chen Y, Liu F, Chen J. Th17 can regulate silica-induced lung inflammation through an IL-1beta-dependent mechanism. J Cell Mol Med. 2014;18(9):1773–84.PubMedPubMedCentralCrossRef
87.
Lu X, McCoy KS, Xu J, Hu W, Chen H, Jiang K, Han F, Chen P, Wang Y. Galectin-9 ameliorates respiratory syncytial virus-induced pulmonary immunopathology through regulating the balance between Th17 and regulatory T cells. Virus Res. 2015;195:162–71.PubMedCrossRef
88.
89.
Vucic EA, Chari R, Thu KL, Wilson IM, Cotton AM, Kennett JY, Zhang M, Lonergan KM, Steiling K, Brown CJ, et al. DNA methylation is globally disrupted and associated with expression changes in chronic obstructive pulmonary disease small airways. Am J Respir Cell Mol Biol. 2014;50(5):912–22.PubMedPubMedCentralCrossRef
90.
91.
92.
Ogura H, Murakami M, Okuyama Y, Tsuruoka M, Kitabayashi C, Kanamoto M, Nishihara M, Iwakura Y, Hirano T. Interleukin-17 promotes autoimmunity by triggering a positive-feedback loop via interleukin-6 induction. Immunity. 2008;29(4):628–36.PubMedCrossRef
93.
Iwakura Y, Ishigame H, Saijo S, Nakae S. Functional specialization of interleukin-17 family members. Immunity. 2011;34(2):149–62.PubMedCrossRef
94.
Kaabachi W, ben Amor A, Kaabachi S, Rafrafi A, Tizaoui K, Hamzaoui K. Interleukin-17A and -17F genes polymorphisms in lung cancer. Cytokine. 2014;66(1):23–9.PubMedCrossRef
95.
96.
Yang XO, Chang SH, Park H, Nurieva R, Shah B, Acero L, Wang YH, Schluns KS, Broaddus RR, Zhu Z, et al. Regulation of inflammatory responses by IL-17F. J Exp Med. 2008;205(5):1063–75.PubMedPubMedCentralCrossRef
97.
Xu C, Hao K, Yu L, Zhang X. Serum interleukin-17 as a diagnostic and prognostic marker for non-small cell lung cancer. Biomarkers. 2014;19(4):287–90.PubMedCrossRef
98.
Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, Wang Y, Hood L, Zhu Z, Tian Q, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005;6(11):1133–41.PubMedPubMedCentralCrossRef
99.
Vucic EA. Multi-omics characterization of the molecular effects of smoking and chronic inflammation on the lung. Vancouver: University of British Columbia; 2014.
100.
Vargas-Rojas MI, Ramirez-Venegas A, Limon-Camacho L, Ochoa L, Hernandez-Zenteno R, Sansores RH. Increase of Th17 cells in peripheral blood of patients with chronic obstructive pulmonary disease. Respir Med. 2011;105(11):1648–54.PubMedCrossRef
101.
Chang SH, Mirabolfathinejad SG, Katta H, Cumpian AM, Gong L, Caetano MS, Moghaddam SJ, Dong C. T helper 17 cells play a critical pathogenic role in lung cancer. Proc Natl Acad Sci U S A. 2014;111(15):5664–9.PubMedPubMedCentralCrossRef
102.
Wei L, Wang H, Yang F, Ding Q, Zhao J. Interleukin-17 potently increases non-small cell lung cancer growth. Mol Med Rep. 2016;13(2):1673–80.PubMed
103.
Reppert S, Boross I, Koslowski M, Tureci O, Koch S, Lehr HA, Finotto S. A role for T-bet-mediated tumour immune surveillance in anti-IL-17A treatment of lung cancer. Nat Commun. 2011;2:600.PubMedCrossRef
104.
Li Q, Han Y, Fei G, Guo Z, Ren T, Liu Z. IL-17 promoted metastasis of non-small-cell lung cancer cells. Immunol Lett. 2012;148(2):144–50.PubMedCrossRef
105.
Pan B, Shen J, Cao J, Zhou Y, Shang L, Jin S, Cao S, Che D, Liu F, Yu Y. Interleukin-17 promotes angiogenesis by stimulating VEGF production of cancer cells via the STAT3/GIV signaling pathway in non-small-cell lung cancer. Sci Rep. 2015;5:16053.PubMedPubMedCentralCrossRef
106.
Gu FM, Li QL, Gao Q, Jiang JH, Zhu K, Huang XY, Pan JF, Yan J, Hu JH, Wang Z, et al. IL-17 induces AKT-dependent IL-6/JAK2/STAT3 activation and tumor progression in hepatocellular carcinoma. Mol Cancer. 2011;10:150.PubMedPubMedCentralCrossRef
107.
Wang L, Yi T, Kortylewski M, Pardoll DM, Zeng D, Yu H. IL-17 can promote tumor growth through an IL-6-Stat3 signaling pathway. J Exp Med. 2009;206(7):1457–64.PubMedPubMedCentralCrossRef
108.
Adams RH, Alitalo K. Molecular regulation of angiogenesis and lymphangiogenesis. Nat Rev Mol Cell Biol. 2007;8(6):464–78.PubMedCrossRef
109.
Chen X, Xie Q, Cheng X, Diao X, Cheng Y, Liu J, Xie W, Chen Z, Zhu B. Role of interleukin-17 in lymphangiogenesis in non-small-cell lung cancer: Enhanced production of vascular endothelial growth factor C in non-small-cell lung carcinoma cells. Cancer Sci. 2010;101(11):2384–90.PubMedCrossRef
110.
Chen X, Wan J, Liu J, Xie W, Diao X, Xu J, Zhu B, Chen Z. Increased IL-17-producing cells correlate with poor survival and lymphangiogenesis in NSCLC patients. Lung Cancer. 2010;69(3):348–54.PubMedCrossRef
111.
Carmi Y, Rinott G, Dotan S, Elkabets M, Rider P, Voronov E, Apte RN. Microenvironment-derived IL-1 and IL-17 interact in the control of lung metastasis. J Immunol. 2011;186(6):3462–71.PubMedCrossRef
112.
Lim C, Savan R. The role of the IL-22/IL-22R1 axis in cancer. Cytokine Growth Factor Rev. 2014;25(3):257–71.PubMedCrossRef
113.
Zhang W, Chen Y, Wei H, Zheng C, Sun R, Zhang J, Tian Z. Antiapoptotic activity of autocrine interleukin-22 and therapeutic effects of interleukin-22-small interfering RNA on human lung cancer xenografts. Clin Cancer Res. 2008;14(20):6432–9.PubMedCrossRef
114.
Martin-Orozco N, Muranski P, Chung Y, Yang XO, Yamazaki T, Lu S, Hwu P, Restifo NP, Overwijk WW, Dong C. T helper 17 cells promote cytotoxic T cell activation in tumor immunity. Immunity. 2009;31(5):787–98.PubMedPubMedCentralCrossRef
115.
Santegoets SJ, Turksma AW, Suhoski MM, Stam AG, Albelda SM, Hooijberg E, Scheper RJ, van den Eertwegh AJ, Gerritsen WR, Powell Jr DJ, et al. IL-21 promotes the expansion of CD27+ CD28+ tumor infiltrating lymphocytes with high cytotoxic potential and low collateral expansion of regulatory T cells. J Transl Med. 2013;11:37.PubMedPubMedCentralCrossRef
116.
Zeng R, Spolski R, Finkelstein SE, Oh S, Kovanen PE, Hinrichs CS, Pise-Masison CA, Radonovich MF, Brady JN, Restifo NP, et al. Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function. J Exp Med. 2005;201(1):139–48.PubMedPubMedCentralCrossRef
117.
Ye ZJ, Zhou Q, Gu YY, Qin SM, Ma WL, Xin JB, Tao XN, Shi HZ. Generation and differentiation of IL-17-producing CD4+ T cells in malignant pleural effusion. J Immunol. 2010;185(10):6348–54.PubMedCrossRef
118.
Galon J, Pages F, Marincola FM, Thurin M, Trinchieri G, Fox BA, Gajewski TF, Ascierto PA. The immune score as a new possible approach for the classification of cancer. J Transl Med. 2012;10:1.PubMedPubMedCentralCrossRef
119.
Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12(4):298–306.PubMedCrossRef
120.
Galon J, Mlecnik B, Bindea G, Angell HK, Berger A, Lagorce C, Lugli A, Zlobec I, Hartmann A, Bifulco C, et al. Towards the introduction of the ‘Immunoscore’ in the classification of malignant tumours. J Pathol. 2014;232(2):199–209.PubMedCrossRef
121.
Donnem T, Kilvaer TK, Andersen S, Richardsen E, Paulsen EE, Hald SM, Al-Saad S, Brustugun OT, Helland A, Lund-Iversen M, et al. Strategies for clinical implementation of TNM-Immunoscore in resected nonsmall-cell lung cancer. Ann Oncol. 2015.
122.
Bryant C, Suen H, Brown R, Yang S, Favaloro J, Aklilu E, Gibson J, Ho PJ, Iland H, Fromm P, et al. Long-term survival in multiple myeloma is associated with a distinct immunological profile, which includes proliferative cytotoxic T-cell clones and a favourable Treg/Th17 balance. Blood Cancer J. 2013;3:e148.PubMedPubMedCentralCrossRef
123.
Zhang W, Hou F, Zhang Y, Tian Y, Jiao J, Ma D, Kong B, Cui B. Changes of Th17/Tc17 and Th17/Treg cells in endometrial carcinoma. Gynecol Oncol. 2014;132(3):599–605.PubMedCrossRef
124.
Wang X, Wang L, Mo Q, Dong Y, Wang G, Ji A. Changes of Th17/Treg cell and related cytokines in pancreatic cancer patients. Int J Clin Exp Pathol. 2015;8(5):5702–8.PubMedPubMedCentral
125.
126.
Li S, Li Y, Qu X, Liu X, Liang J. Detection and significance of TregFoxP3(+) and Th17 cells in peripheral blood of non-small cell lung cancer patients. Arch Med Sci. 2014;10(2):232–9.PubMedPubMedCentralCrossRef
127.
128.
Szodoray P, Nakken B, Barath S, Csipo I, Nagy G, El-Hage F, Osnes LT, Szegedi G, Bodolay E. Altered Th17 cells and Th17/regulatory T-cell ratios indicate the subsequent conversion from undifferentiated connective tissue disease to definitive systemic autoimmune disorders. Hum Immunol. 2013;74(12):1510–8.PubMedCrossRef
129.
Xing Q, Wang B, Su H, Cui J, Li J. Elevated Th17 cells are accompanied by FoxP3+ Treg cells decrease in patients with lupus nephritis. Rheumatol Int. 2012;32(4):949–58.PubMedCrossRef
130.
Astry B, Venkatesha SH, Moudgil KD. Involvement of the IL-23/IL-17 axis and the Th17/Treg balance in the pathogenesis and control of autoimmune arthritis. Cytokine. 2015;74(1):54–61.PubMedPubMedCentralCrossRef
131.
Su ZJ, Yu XP, Guo RY, Ming DS, Huang LY, Su ML, Deng Y, Lin ZZ. Changes in the balance between Treg and Th17 cells in patients with chronic hepatitis B. Diagn Microbiol Infect Dis. 2013;76(4):437–44.PubMedCrossRef
132.
Xu L, Gong Y, Wang B, Shi K, Hou Y, Wang L, Lin Z, Han Y, Lu L, Chen D, et al. Randomized trial of autologous bone marrow mesenchymal stem cells transplantation for hepatitis B virus cirrhosis: regulation of Treg/Th17 cells. J Gastroenterol Hepatol. 2014;29(8):1620–8.PubMedCrossRef
133.
Pang N, Zhang F, Ma X, Zhu Y, Zhao H, Xin Y, Wang S, Chen Z, Wen H, Ding J. TGF-beta/Smad signaling pathway regulates Th17/Treg balance during Echinococcus multilocularis infection. Int Immunopharmacol. 2014;20(1):248–57.PubMedCrossRef
134.
Gil JH, Seo JW, Cho MS, Ahn JH, Sung HY. Role of Treg and TH17 cells of the gastric mucosa in children with Helicobacter pylori gastritis. J Pediatr Gastroenterol Nutr. 2014;58(2):245–51.PubMedCrossRef
135.
136.
137.
Duan MC, Han W, Jin PW, Wei YP, Wei Q, Zhang LM, Li JC. Disturbed Th17/Treg balance in patients with non-small cell lung cancer. Inflammation. 2015;38(6):2156–65.PubMedCrossRef
138.
Prado-Garcia H, Romero-Garcia S, Rumbo-Nava U, Lopez-Gonzalez JS. Predominance of Th17 over regulatory T-cells in pleural effusions of patients with lung cancer implicates a proinflammatory profile. Anticancer Res. 2015;35(3):1529–35.PubMed
139.
Yang G, Li H, Yao Y, Xu F, Bao Z, Zhou J. Treg/Th17 imbalance in malignant pleural effusion partially predicts poor prognosis. Oncol Rep. 2015;33(1):478–84.PubMed
140.
Crusz SM, Balkwill FR. Inflammation and cancer: advances and new agents. Nat Rev Clin Oncol. 2015;12(10):584–96.PubMedCrossRef
141.
Crowley E, Di Nicolantonio F, Loupakis F, Bardelli A. Liquid biopsy: monitoring cancer-genetics in the blood. Nat Rev Clin Oncol. 2013;10(8):472–84.PubMedCrossRef
142.
Newell EW, Davis MM. Beyond model antigens: high-dimensional methods for the analysis of antigen-specific T cells. Nat Biotechnol. 2014;32(2):149–57.PubMedPubMedCentralCrossRef
143.
Kroeger DR, Milne K, Nelson BH. Tumor-infiltrating plasma cells are associated with tertiary lymphoid structures, cytolytic T-cell responses, and superior prognosis in ovarian cancer. Clin Cancer Res. 2016;22(12):3005–15.PubMedCrossRef
144.
Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, Chmielowski B, Spasic M, Henry G, Ciobanu V, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515(7528):568–71.PubMedPubMedCentralCrossRef
145.
Kryczek I, Wu K, Zhao E, Wei S, Vatan L, Szeliga W, Huang E, Greenson J, Chang A, Rolinski J, et al. IL-17+ regulatory T cells in the microenvironments of chronic inflammation and cancer. J Immunol. 2011;186(7):4388–95.PubMedCrossRef
146.
Du R, Zhao H, Yan F, Li H. IL-17 + Foxp3+ T cells: an intermediate differentiation stage between Th17 cells and regulatory T cells. J Leukoc Biol. 2014;96(1):39–48.PubMedCrossRef
147.
Hovhannisyan Z, Treatman J, Littman DR, Mayer L. Characterization of interleukin-17-producing regulatory T cells in inflamed intestinal mucosa from patients with inflammatory bowel diseases. Gastroenterology. 2011;140(3):957–65.PubMedCrossRef
148.
Li L, Boussiotis VA. The role of IL-17-producing Foxp3+ CD4+ T cells in inflammatory bowel disease and colon cancer. Clin Immunol. 2013;148(2):246–53.PubMedCrossRef
149.
Huang C, Fu ZX. Localization of IL-17 + Foxp3+ T cells in esophageal cancer. Immunol Invest. 2011;40(4):400–12.PubMedCrossRef
150.
Girardin A, McCall J, Black MA, Edwards F, Phillips V, Taylor ES, Reeve AE, Kemp RA. Inflammatory and regulatory T cells contribute to a unique immune microenvironment in tumor tissue of colorectal cancer patients. Int J Cancer. 2013;132(8):1842–50.PubMedCrossRef
151.
Phillips JD, Knab LM, Blatner NR, Haghi L, DeCamp MM, Meyerson SL, Heiferman MJ, Heiferman JR, Gounari F, Bentrem DJ, et al. Preferential expansion of pro-inflammatory Tregs in human non-small cell lung cancer. Cancer Immunol Immunother. 2015;64(9):1185–91.PubMedPubMedCentralCrossRef
152.
Smyth MJ, Ngiow SF, Teng MW. Targeting regulatory T cells in tumor immunotherapy. Immunol Cell Biol. 2014;92(6):473–4.PubMedCrossRef
153.
Lin H, Song P, Zhao Y, Xue LJ, Liu Y, Chu CQ. Targeting Th17 Cells with Small Molecules and Small Interference RNA. Mediators Inflamm. 2015;2015:290657.PubMedPubMedCentral
154.
Onishi H, Morisaki T, Katano M. Immunotherapy approaches targeting regulatory T-cells. Anticancer Res. 2012;32(3):997–1003.PubMed
155.
156.
Xu J, Yin Z, Cao S, Gao W, Liu L, Yin Y, Liu P, Shu Y. Systematic review and meta-analysis on the association between IL-1B polymorphisms and cancer risk. PLoS One. 2013;8(5):e63654.PubMedPubMedCentralCrossRef
157.
Yu Z, Liu Q, Huang C, Wu M, Li G. The interleukin 10–819C/T polymorphism and cancer risk: a HuGE review and meta-analysis of 73 studies including 15,942 cases and 22,336 controls. OMICS. 2013;17(4):200–14.PubMedPubMedCentralCrossRef
158.
159.
Oft M. IL-10: master switch from tumor-promoting inflammation to antitumor immunity. Cancer Immunol Res. 2014;2(3):194–9.PubMedCrossRef
160.
Zhang J, Patel L, Pienta KJ. CC chemokine ligand 2 (CCL2) promotes prostate cancer tumorigenesis and metastasis. Cytokine Growth Factor Rev. 2010;21(1):41–8.PubMedCrossRef
161.
Steiner JL, Murphy EA. Importance of chemokine (CC-motif) ligand 2 in breast cancer. Int J Biol Markers. 2012;27(3):e179–85.PubMedCrossRef
162.
163.
Verbeke H, Geboes K, Van Damme J, Struyf S. The role of CXC chemokines in the transition of chronic inflammation to esophageal and gastric cancer. Biochim Biophys Acta. 2012;1825(1):117–29.PubMed
164.
Aliper AM, Frieden-Korovkina VP, Buzdin A, Roumiantsev SA, Zhavoronkov A. A role for G-CSF and GM-CSF in nonmyeloid cancers. Cancer Med. 2014;3(4):737–46.PubMedPubMedCentralCrossRef
165.
Shojaei F, Wu X, Qu X, Kowanetz M, Yu L, Tan M, Meng YG, Ferrara N. G-CSF-initiated myeloid cell mobilization and angiogenesis mediate tumor refractoriness to anti-VEGF therapy in mouse models. Proc Natl Acad Sci U S A. 2009;106(16):6742–7.PubMedPubMedCentralCrossRef
166.
Rodvold JJ, Mahadevan NR, Zanetti M. Lipocalin 2 in cancer: when good immunity goes bad. Cancer Lett. 2012;316(2):132–8.PubMedCrossRef
167.
Leng X, Wu Y, Arlinghaus RB. Relationships of lipocalin 2 with breast tumorigenesis and metastasis. J Cell Physiol. 2011;226(2):309–14.PubMedCrossRef
168.
Bose SK, Gibson W, Bullard RS, Donald CD. PAX2 oncogene negatively regulates the expression of the host defense peptide human beta defensin-1 in prostate cancer. Mol Immunol. 2009;46(6):1140–8.PubMedCrossRef
169.
Yang D, Biragyn A, Hoover DM, Lubkowski J, Oppenheim JJ. Multiple roles of antimicrobial defensins, cathelicidins, and eosinophil-derived neurotoxin in host defense. Annu Rev Immunol. 2004;22:181–215.PubMedCrossRef
Metadata
Title
Emerging roles of T helper 17 and regulatory T cells in lung cancer progression and metastasis
Authors
Erin A. Marshall
Kevin W. Ng
Sonia H. Y. Kung
Emma M. Conway
Victor D. Martinez
Elizabeth C. Halvorsen
David A. Rowbotham
Emily A. Vucic
Adam W. Plumb
Daiana D. Becker-Santos
Katey S. S. Enfield
Jennifer Y. Kennett
Kevin L. Bennewith
William W. Lockwood
Stephen Lam
John C. English
Ninan Abraham
Wan L. Lam
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2016
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-016-0551-1

Other articles of this Issue 1/2016

Molecular Cancer 1/2016 Go to the issue

Letter to the Editor

Small non-coding RNA biomarkers in sputum for lung cancer diagnosis

Research

Acidic tumor microenvironment abrogates the efficacy of mTORC1 inhibitors

Research

Inhibition of BMP and of TGFβ receptors downregulates expression of XIAP and TAK1 leading to lung cancer cell death

Erratum

Erratum to: ‘Deregulation of the FOXM1 target gene network and its coregulatory partners in oesophageal adenocarcinoma’

Letter to the Editor

Comprehensive screening of target molecules by next-generation sequencing in patients with malignant solid tumors: guiding entry into phase I clinical trials

Research

Rac1-mediated cytoskeleton rearrangements induced by intersectin-1s deficiency promotes lung cancer cell proliferation, migration and metastasis
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits