Journal of Prevention and Treatment for Stomatological Diseases ›› 2019, Vol. 27 ›› Issue (2): 115-121.doi: 10.12016/j.issn.2096-1456.2019.02.010

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Research progress on the CD4 +T cell balance in oral cancer and precancerous diseases

TIAN Yuanye,TANG Zhangui()   

  1. Department of Oral and Maxillofacial Surgery, Xiangya Stomatological Hospital, Central South University, Changsha 410078, China
  • Received:2018-06-11 Revised:2018-07-17 Online:2019-02-20 Published:2019-02-21
  • Contact: Zhangui TANG


CD4 +T cells play an important role in regulating adaptive immune responses to various inflammatory responses. Parental T cell populations can differentiate in response to different cytokines into at least four subpopulations: Th1, Th2, Th17, and Treg cells. These differentiated T cells participate in various immune responses and have different roles and functions in oral cancer and precancerous diseases. The Th1/Th2 balance, the Th17/Treg balance and the occurrence and development of oral cancer and precancerous diseases are related to immune imbalances. Reversing these T cell imbalances and strengthening the patient’s autoimmune function may prevent or even reverse the progression of oral and precancerous diseases. This paper reviews the research advances on the CD4 +T cell balance in oral cancer and precancerous lesions.

Key words: Th1, Th2, Th17, Regulatory T cell, Oral squamous cell carcinoma, Oral precancerous lesion

CLC Number: 

  • R739.8
[1] Abbas AK, Murphy KM, Sher A . Functional diversity of helper T lymphocytes[J]. Nature, 1996,383(663):787-793.
doi: 10.1038/383787a0
[2] Arbore G, West EE, Spolski R , et al. T helper 1 immunity requires complement-driven NLRP3 inflammasome activity in CD4 + T cells[J]. Science, 2016, 352(6292): aad1210.
doi: 10.1126/science.aad1210 pmid: 5015487
[3] Peng D, Kryczek I, Nagarsheth N , et al. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy[J]. Nature, 2015,527(7577):249-253.
doi: 10.1038/nature15520 pmid: 26503055
[4] Mandai M, Hamanishi J, Abiko K , et al. Dual faces of IFNγ in cancer progression: a role of PD-L1 induction in the determination of pro- and antitumor immunity[J]. Clin Cancer Res, 2016,22(10):2329-2334.
doi: 10.1158/1078-0432.CCR-16-0224
[5] Gao J, Shi LZ, Zhao H , et al. Loss of IFN-γ pathway genes in tumor cells as a mechanism of resistance to anti-CTLA-4 therapy[J]. Cell, 2016,167(2):397-404.
doi: 10.1016/j.cell.2016.08.069 pmid: 27667683
[6] Peng M, Yin N, Chhangawala S , et al. Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism[J]. Science, 2016,354(6311):481-484.
doi: 10.1126/science.aaf6284 pmid: 5539971
[7] Zhu J, Yamane H, Paul WE . Differentiation of effector CD4 T cell populations[J]. Annu Rev Immunol, 2010,28(28):445-489.
doi: 10.1146/annurev-immunol-030409-101212
[8] Nakayama T, Hirahara K, Onodera A , et al. Th2 cells in health and disease[J]. Annu Rev Immunol, 2017,35:53-84.
doi: 10.1146/annurev-immunol-051116-052350 pmid: 27912316
[9] Wynn TA . Type 2 cytokines: mechanisms and therapeutic strategies[J]. Nat Rev Immunol, 2015,15(5):271-282.
doi: 10.1038/nri3831 pmid: 25882242
[10] Van Dyken SJ, Locksley RM . Interleukin-4- and interleukin-13-mediated alternatively activated macrophages: roles in homeostasis and disease[J]. Annu Rev Immunol, 2013,31:317-343.
doi: 10.1146/annurev-immunol-032712-095906 pmid: 3606684
[11] Mills EL, O'neill LA . Reprogramming mitochondrial metabolism in macrophages as an anti-inflammatory signal[J]. Eur J Immunol, 2016,46(1):13-21.
doi: 10.1002/eji.201445427 pmid: 26643360
[12] Draghiciu O, Lubbers J, Nijman HW , et al. Myeloid derived suppressor cells-an overview of combat strategies to increase immunotherapy efficacy[J]. Oncoimmunology, 2015,4(1):e954829.
doi: 10.4161/21624011.2014.954829 pmid: 25949858
[13] Raphael I, Nalawade S, Eagar TN , et al. T cell subsets and their signature cytokines in autoimmune and inflammatory diseases[J]. Cytokine, 2015,74(1):5-17.
doi: 10.1016/j.cyto.2014.09.011 pmid: 4416069
[14] Tran GT, Hodgkinson SJ, Carter NM , et al. IL-5 promotes induction of antigen-specific CD4 +CD25 + T regulatory cells that suppress autoimmunity [J]. Blood, 2012,119(19):4441-4450.
doi: 10.1182/blood-2011-12-396101 pmid: 22310911
[15] Wawrzyniak P, Wawrzyniak M, Wanke K , et al. Regulation of bronchial epithelial barrier integrity by type 2 cytokines and histone deacetylases in asthmatic patients[J]. J Allergy Clin Immunol, 2017,139(1):93-103.
doi: 10.1016/j.jaci.2016.03.050 pmid: 27312821
[16] Serafini N, Vosshenrich CA, Di Santo JP . Transcriptional regulation of innate lymphoid cell fate[J]. Nat Rev Immunol, 2015,15(7):415-428.
doi: 10.1038/nri3855 pmid: 26065585
[17] Krug N, Hohlfeld JM, Kirsten AM , et al. Allergen-induced asthmatic responses modified by a GATA3-specific DNAzyme[J]. N Engl J Med, 2015,372(21):1987-1995.
doi: 10.1056/NEJMoa1411776 pmid: 25981191
[18] Tremblay, Bouchard. GATA3(GATA binding protein 3)[J]. Atlas Genet Cytogenet Oncol Haematol. , 2012,16(5):342-346.
doi: 10.1007/978-1-4419-0461-4_29
[19] Patel DD, Kuchroo VK . Th17 cell pathway in human immunity: lessons from genetics and therapeutic interventions[J]. Immunity, 2015,43(6):1040-1051.
doi: 10.1016/j.immuni.2015.12.003 pmid: 26682981
[20] Maddur MS, Miossec P, Kaveri SV , et al. Th17 cells: biology, pathogenesis of autoimmune and inflammatory diseases, and therapeutic strategies[J]. AmJ Pathol, 2012,181(1):8-18.
doi: 10.1016/j.ajpath.2012.03.044
[21] Liu HP, Cao AT, Feng T , et al. TGF-β converts Th1 cells into Th17 cells through stimulation of Runx1 expression[J]. Eur J Immunol, 2015,45(4):1010-1018.
doi: 10.1002/eji.201444726
[22] 张蓝方, 郝云良 . Th17/Treg平衡调节与疾病的关系研究进展[J]. 济宁医学院学报, 2011,34(1):68-71.
doi: 10.3969/j.issn.1000-9760.2011.01.025
[23] Zhang L, Yan J, Yang B , et al. IL-23 activated γδ T cells affect Th17 cells and regulatory T cells by secreting IL-21 in children with primary nephrotic syndrome[J]. Scand J Immunol, 2018,87(1):36-45.
doi: 10.1111/sji.12629 pmid: 29119640
[24] Veldhoen M . Interleukin 17 is a chief orchestrator of immunity[J]. Nat Immunol, 2017,18(6):612-621.
doi: 10.1038/ni.3742 pmid: 28518156
[25] Liu X, Hu H, Fan H , et al. The role of STAT3 and AhR in the differentiation of CD4 + T cells into Th17 and Treg cells [J]. Medicine, 2017,96(17):e6615.
doi: 10.1097/MD.0000000000006615 pmid: 5413224
[26] Li MO, Rudensky AY . T cell receptor signalling in the control of regulatory T cell differentiation and function[J]. Nat Rev Immunol, 2016,16(4):220-233.
doi: 10.1038/nri.2016.26 pmid: 27026074
[27] Hong JW, Lim JH, Chung CJ , et al. Immune tolerance of human dental pulp-derived mesenchymal stem cells mediated by CD4 +CD25 +FoxP3 + regulatory T-Cells and induced by TGF-β1 and IL-10 [J]. Yonsei Med J, 2017,58(5):1031-1039.
doi: 10.3349/ymj.2017.58.5.1031
[28] Guan SY, Leng RX, Khan MI , et al. Interleukin-35: a potential therapeutic agent for autoimmune diseases[J]. Inflammation, 2017,40(1):303-310.
doi: 10.1007/s10753-016-0453-9 pmid: 27696334
[29] Gerriets VA, Kishton RJ, Johnson MO , et al. Foxp3 and toll-like receptor signaling balance Treg cell anabolic metabolism for suppression[J]. Nat Immunol, 2016,17(12):1459-1466.
doi: 10.1038/ni.3577 pmid: 27695003
[30] Kitagawa Y, Sakaguchi S . Molecular control of regulatory T cell development and function[J]. Curr Opin Immunol, 2017,49:64-70.
doi: 10.1016/j.coi.2017.10.002 pmid: 29065384
[31] Li S, Lee YC, Li Q , et al. Oral lesions, chronic diseases and the risk of head and neck cancer[J]. Oral Oncol, 2015,51(12):1082-1087
doi: 10.1016/j.oraloncology.2015.10.014 pmid: 26526128
[32] Yeh CY, Lin CL, Chang MC , et al. Differences in oral habit and lymphocyte subpopulation affect malignant transformation of patients with oral precancer[J]. J Formos Med Assoc, 2016,115(4):263-268.
doi: 10.1016/j.jfma.2015.07.017 pmid: 26412231
[33] Sakaguchi S, Yamaguchi T, Nomura T , et al. Regulatory T cells and immune tolerance[J]. Cell, 2008,133(5):775-787.
doi: 10.1016/j.cell.2008.05.009 pmid: 18510923
[34] Ku CM, Lin JY . Anti-inflammatory effects of 27 selected terpenoid compounds tested through modulating Th1/Th2 cytokine secretion profiles using murine primary splenocytes[J]. Food Chem , 2013,141(2):1104-1113.
doi: 10.1016/j.foodchem.2013.04.044
[35] Vinay DS, Ryan EP, Pawelec G , et al. Immune evasion in cancer: mechanistic basis and therapeutic strategies[C]. Seminars in cancer biology. Academic Press, 2015,35:S185-S198.
[36] Young M, Levingston CA, Johnson SD . Treatment to sustain a Th17-type phenotype to prevent skewing toward Treg and to limit premalignant lesion progression to cancer[J]. Int J Cancer, 2016,138(10):2487-2498.
doi: 10.1002/ijc.29989 pmid: 26756968
[37] Gaur P, Qadir GA, Upadhyay S , et al. Skewed immunological balance between Th17 (CD4(+) IL17A(+)) and Treg (CD4 (+) CD25(+) FOXP3(+)) cells in human oral squamous cell carcinoma[J]. Cell Oncol (Dordr), 2012,35(5):335-343.
doi: 10.1007/s13402-012-0093-5 pmid: 22956260
[38] Johnson SD, De Costa AM, Young MR . Effect of the premalignant and tumor microenvironment on immune cell cytokine production in head and neck cancer[J]. Cancers (Basel), 2014,6(2):756-770.
doi: 10.3390/cancers6020756 pmid: 4074802
[39] Wei W, Sun Q, Deng Y , et al. Mixed and inhomogeneous expression profile of Th1/Th2 related cytokines detected by cytometric bead array in the saliva of patients with oral lichen planus[J]. Oral Surg Oral Med Oral Pathol Oral Radiol, 2018,126(2):142-151.
doi: 10.1016/j.oooo.2018.02.013 pmid: 29627199
[40] 方溢云 . 口腔扁平苔藓外周血Th1/Th2型细胞因子表达水平的价值研究[J]. 现代诊断与治疗, 2017,28(14):2660-2661.
[41] Enomoto A, Sato E, Yasuda T , et al. Intraepithelial CD8 + lymphocytes as a predictive diagnostic biomarker for the remission of oral lichen planus [J]. Hum Pathol, 2018,74:43-53.
doi: 10.1016/j.humpath.2017.12.008 pmid: 29288692
[42] Gueiros LA, Arão T, Souza T , et al. IL 17A polymorphism and elevated IL 17A serum levels are associated with oral lichen planus[J]. Oral Dis, 2018,24(3):377-383.
doi: 10.1111/odi.12718 pmid: 28741807
[43] Pekiner FN, Demirel GY, Borahan MO , et al. Cytokine profiles in serum of patients with oral lichen planus[J]. Cytokine, 2012,60(3):701-706.
doi: 10.1016/j.cyto.2012.08.007 pmid: 22995209
[44] Ai R, Tao Y, Hao Y , et al. Microenvironmental regulation of the progression of oral potentially malignant disorders towards malignancy[J]. Oncotarget, 2017,8(46):81617-81635
doi: 10.18632/oncotarget.20312 pmid: 5655314
[45] Wang H, Zhang D, Han Q , et al. Role of distinct CD4(+) T helper subset in pathogenesis of oral lichen planus[J]. J Oral Pathol Med, 2016,45(6):385-393.
doi: 10.1111/jop.12405 pmid: 26693958
[46] 陶小安, 肖建勇, 曾琪 , 等. 口腔扁平苔藓中乳腺珠蛋白表达变化的初步研究[J]. 中华口腔医学杂志, 2013,48(10):606-609.
doi: 10.3760/cma.j.issn.1002-0098.2013.10.007
[47] El-Sakka H, Kujan O, Farah CS . Assessing miRNAs profile expression as a risk stratification biomarker in oral potentially malignant disorders: a systematic review[J]. Oral Oncol, 2018,77:57-82.
doi: 10.1016/j.oraloncology.2017.11.021 pmid: 29362128
[48] Haque M, Harris M, Henderson B , et al. An immunohistochemical study of inflammatory cells in oral subcumous fibrosis[J]. Acta Histochem, 1995,114(6):571-576.
doi: 10.1016/j.acthis.2011.10.007
[49] Ferlay J, Soerjomataram I, Dikshit R , et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012[J]. Int J Cancer, 2015,136(5):E359-E386.
doi: 10.1002/ijc.29210
[50] Kumar S, Saini RV, Mahindroo N . Recent advances in cancer immunology and immunology-based anticancer therapies[J]. BioMed Pharmacother, 2017,96:1491-1500.
doi: 10.1016/j.biopha.2017.11.126 pmid: 29198747
[51] Gaur P, Singh AK, Shukla NK , et al. Inter-relation of Th1, Th2, Th17 and Treg cytokines in oral cancer patients and their clinical significance[J]. Hum Immunol, 2014,75(4):330-337.
doi: 10.1016/j.humimm.2014.01.011 pmid: 24486578
[52] Sun W, Li WJ, Fu QL , et al. Functionally distinct subsets of CD4 + regulatory T cells in patients with laryngeal squamous cell carcinoma are indicative of immune deregulation and disease progression [J]. Oncol Rep, 2015,33(1):354-362.
doi: 10.3892/or.2014.3553 pmid: 25333227
[53] 张素欣, 包阳, 张敬 , 等. 口腔鳞癌患者外周血及癌组织中IL-17和Foxp3的表达及意义[J]. 肿瘤防治研究, 2015,42(3):246-251.
doi: 10.3971/j.issn.1000-8578.2015.03.008
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