Treg/Th17 imbalance in malignant pleural effusion partially predicts poor prognosis

Yang,Guangdie; Li,Hequan; Yao,Yinan; Xu,Fei; Bao,Zhang; Zhou,Jianying

doi:10.3892/or.2014.3576

Treg/Th17 imbalance in malignant pleural effusion partially predicts poor prognosis

Authors:
- Guangdie Yang
- Hequan Li
- Yinan Yao
- Fei Xu
- Zhang Bao
- Jianying Zhou
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Affiliations: Department of Respiratory Diseases, First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
Published online on: October 30, 2014 https://doi.org/10.3892/or.2014.3576
Pages: 478-484

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Abstract

Accumulating evidence shows that an imbalance in regulatory T cells (Tregs)/T helper IL-17-producing cells (Th17) exists in malignant pleural effusion (MPE). However, the cause of this phenomenon in MPE and the underlying mechanism remain uncertain. The percentages of Tregs and Th17 cells in MPE and parapneumonic effusion (PPE) were determined by flow cytometry. Their specific transcription factors, forkhead box P3 (FoxP3) and retinoic acid-related orphan receptor γt (RORγt); related cytokines, interleukin-6 (IL-6), IL-17, IL-10, and transforming growth factor-β1 (TGF‑β1); and chemokines, C-C motif ligand 17 (CCL17) and CCL20, were analyzed by real-time PCR and ELISA, respectively. Compared to patients with PPE, patients with MPE presented a higher percentage of Tregs but a lower frequency of Th17 cells. Foxp3 mRNA expression level in the cells in the pleural effusion was significantly increased in patients with MPE compared to the levels in patients with PPE (MPE vs. PPE: 3.05±0.62 vs. 0.52±0.11, p=0.0012). It was also noted that high levels of IL-10, TGF-β1 and CCL17 were observed in MPE when compared to PPE (MPE vs. PPE: IL-10, 166.3±39.53 vs. 40.38±10.92 pg/ml, p=0.0307; TGF-β1, 10,720±1,274 vs. 1,747±293.2 pg/ml, p<0.0001; CCL17, 341.1±88.22 vs. 119.2±19.80 pg/ml, p=0.0427). Furthermore, a high ratio of Tregs/Th17 cells in MPE was highly correlated to poor survival. An alteration in CCL17 and CCL20 might contribute to the Treg/Th17 imbalance in MPE, which partially predicts a poor prognosis in patients with lung cancer.

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1	Roberts ME, Neville E, Berrisford RG, Antunes G and Ali NJ: BTS Pleural Disease Guideline Group: Management of a malignant pleural effusion: British Thoracic Society Pleural Disease Guideline 2010. Thorax. 65:ii32–ii40. 2010. View Article : Google Scholar
2	Bielsa S, Martín-Juan J, Porcel JM and Rodríguez-Panadero F: Diagnostic and prognostic implications of pleural adhesions in malignant effusions. J Thorac Oncol. 3:1251–1256. 2008. View Article : Google Scholar : PubMed/NCBI
3	Marazioti A, Blackwell TS and Stathopoulos GT: The lymphatic system in malignant pleural effusion. Drain or immune switch? Am J Respir Crit Care Med. 189:626–627. 2014. View Article : Google Scholar : PubMed/NCBI
4	Aguiar LM, Antonangelo L, Vargas FS, Zerbini MC, Sales MM, Uip DE and Saldiva PH: Malignant and tuberculous pleural effusions: immunophenotypic cellular characterization. Clinics (Sao Paulo). 63:637–644. 2008. View Article : Google Scholar
5	Muller YD, Seebach JD, Bühler LH, Pascual M and Golshayan D: Transplantation tolerance: clinical potential of regulatory T cells. Self Nonself. 2:26–34. 2011. View Article : Google Scholar : PubMed/NCBI
6	Gregori S, Bacchetta R, Passerini L, Levings MK and Roncarolo MG: Isolation, expansion, and characterization of human natural and adaptive regulatory cells. Methods Mol Biol. 380:83–106. 2007. View Article : Google Scholar
7	Wilke CM, Wu K, Zhao E, Wang G and Zou W: Prognostic significance of regulatory T cells in tumor. Int J Cancer. 127:748–758. 2010.PubMed/NCBI
8	Qin XJ, Shi HZ, Deng JM, Liang QL, Jiang J and Ye ZJ: CCL22 recruits CD4-positive CD25-positive regulatory T cells into malignant pleural effusion. Clin Cancer Res. 15:2231–2237. 2009. View Article : Google Scholar : PubMed/NCBI
9	Bettelli E, Oukka M and Kuchroo VK: T_H-17 cells in the circle of immunity and autoimmunity. Nat Immunol. 8:345–350. 2007. View Article : Google Scholar : PubMed/NCBI
10	Kryczek I, Banerjee M, Cheng P, et al: Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments. Blood. 114:1141–1149. 2009. View Article : Google Scholar : PubMed/NCBI
11	Ye ZJ, Zhou Q, Gu YY, et al: Generation and differentiation of IL-17-producing CD4⁺ T cells in malignant pleural effusion. J Immunol. 185:6348–6354. 2010. View Article : Google Scholar : PubMed/NCBI
12	Mizukami Y, Kono K, Kawaguchi Y, Akaike H, Kamimura K, Sugai H and Fujii H: CCL17 and CCL22 chemokines within tumor microenvironment are related to accumulation of Foxp3⁺ regulatory T cells in gastric cancer. Int J Cancer. 122:2286–2293. 2008. View Article : Google Scholar : PubMed/NCBI
13	Lin X, Chen M, Liu Y, Guo Z, He X, Brand D and Zheng SG: Advances in distinguishing natural from induced Foxp3⁺ regulatory T cells. Int J Clin Exp Pathol. 6:116–123. 2013.
14	Larmonier N, Marron M, Zeng Y, et al: Tumor-derived CD4⁺CD25⁺ regulatory T cell suppression of dendritic cell function involves TGF-beta and IL-10. Cancer Immunol Immunother. 56:48–59. 2007. View Article : Google Scholar
15	Badoual C, Hans S, Rodriguez J, et al: Prognostic value of tumor-infiltrating CD4⁺ T-cell subpopulations in head and neck cancers. Clin Cancer Res. 12:465–472. 2006. View Article : Google Scholar : PubMed/NCBI
16	Kosmaczewska A, Ciszak L, Potoczek S and Frydecka I: The significance of Treg cells in defective tumor immunity. Arch Immunol Ther Exp (Warsz). 56:181–191. 2008. View Article : Google Scholar
17	Ibrahim L, Salah M, Rahman AA, Zeidan A and Ragb M: Crucial role of CD4⁺CD25⁺ FOXP3⁺ T regulatory cell, interferon-γ and interleukin-16 in malignant and tuberculous pleural effusions. Immunol Invest. 42:122–136. 2013. View Article : Google Scholar
18	Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM and Weaver CT: 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. 2005. View Article : Google Scholar : PubMed/NCBI
19	Prabhala RH, Pelluru D, Fulciniti M, et al: Elevated IL-17 produced by TH17 cells promotes myeloma cell growth and inhibits immune function in multiple myeloma. Blood. 115:5385–5392. 2010. View Article : Google Scholar : PubMed/NCBI
20	Tosolini M, Kirilovsky A, Mlecnik B, et al: Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer. Cancer Res. 71:1263–1271. 2011. View Article : Google Scholar : PubMed/NCBI
21	Qi W, Huang X and Wang J: Correlation between Th17 cells and tumor microenvironment. Cell Immunol. 285:18–22. 2013. View Article : Google Scholar : PubMed/NCBI
22	Iida T, Iwahashi M, Katsuda M, et al: Tumor-infiltrating CD4⁺ Th17 cells produce IL-17 in tumor microenvironment and promote tumor progression in human gastric cancer. Oncol Rep. 25:1271–1217. 2011. View Article : Google Scholar : PubMed/NCBI
23	Gu FM, Li QL, Gao Q, et al: IL-17 induces AKT-dependent IL-6/ JAK2/STAT3 activation and tumor progression in hepatocellular carcinoma. Mol Cancer. 10:1502011. View Article : Google Scholar
24	Martin-Orozco N, Muranski P, et al: T helper 17 cells promote cytotoxic T cell activation in tumor immunity. Immunity. 31:787–798. 2009. View Article : Google Scholar : PubMed/NCBI
25	Ayyoub M, Deknuydt F, Raimbaud I, Dousset C, Leveque L, Bioley G and Valmori D: Human memory FOXP3⁺ Tregs secrete IL-17 ex vivo and constitutively express the T_H17 lineage- specific transcription factor RORγt. Proc Natl Acad Sci USA. 106:8635–8640. 2009. View Article : Google Scholar
26	Weaver CT and Hatton RD: Interplay between the TH17 and TReg cell lineages: a (co-) evolutionary perspective. Nat Rev Immunol. 9:883–889. 2009. View Article : Google Scholar : PubMed/NCBI
27	Zhou L, Lopes JE, Chong MM, et al: TGF-beta-induced Foxp3 inhibits T_H17 cell differentiation by antagonizing RORγt function. Nature. 453:236–240. 2008. View Article : Google Scholar : PubMed/NCBI
28	Kimura A and Kishimoto T: IL-6: regulator of Treg/Th17 balance. Eur J Immunol. 40:1830–1835. 2010. View Article : Google Scholar : PubMed/NCBI
29	Smith AL, Robin TP and Ford HL: Molecular pathways: targeting the TGF-β pathway for cancer therapy. Clin Cancer Res. 18:4514–4521. 2012. View Article : Google Scholar : PubMed/NCBI
30	Hamidullah, Changkija B and Konwar R: Role of interleukin-10 in breast cancer. Breast Cancer Res Treat. 133:11–21. 2012. View Article : Google Scholar
31	Olkhanud PB, Baatar D, Bodogai M, et al: Breast cancer lung metastasis requires expression of chemokine receptor CCR4 and regulatory T cells. Cancer Res. 69:5996–6004. 2009. View Article : Google Scholar : PubMed/NCBI
32	Curiel TJ, Coukos G, Zou L, et al: Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 10:942–949. 2004. View Article : Google Scholar : PubMed/NCBI
33	Franciszkiewicz K, Boissonnas A, Boutet M, Combadière C and Mami-Chouaib F: Role of chemokines and chemokine receptors in shaping the effector phase of the antitumor immune response. Cancer Res. 72:6325–6332. 2012. View Article : Google Scholar : PubMed/NCBI