Skip to main content

Advertisement

SpringerLink
Log in

Dysregulation of helper T lymphocytes in esophageal squamous cell carcinoma (ESCC) patients is highly associated with aberrant production of miR-21

  • Original Article
  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

Dysregulation of helper T (Th) cell subsets has been contributed to the initiation and propagation of esophageal squamous cell carcinoma (ESCC). Different microRNAs (miRNAs) have been reported to control the development and functions of tumor-associated immune cells in ESCC. Here, we aimed to assess the IL-10, TGF-β, IFN-γ, and IL-17a-producing CD3+CD8− T cells in association whit miR-21, miR-29b, miR-106a, and miR-155 expression in ESCC patients. A total of 34 ESCC patients including 12 newly diagnosed (ND) and 22 under-treatment (UT) cases and also 34 age-matched healthy donors were enrolled. Flow cytometric characterization of stimulated T cells was performed by staining of the cells with fluorescent conjugated specific anti-human CD3 and CD8 cell surface markers as well as IL-17a, IFN-γ, IL-10, and TGF-β intracytoplasmic cytokines. Circulating RNA was extracted from the plasma, and qRT-PCR was used to evaluate the expression of microRNAs. TGF-β plasma levels were also assessed by ELISA. Results showed that the frequency of Th cells was significantly reduced in patients. A significant increase in Treg as well as Th17 cells population in both patient subgroups was observed. ND patients showed elevated level of Th1 cells and IL-10. However the mean expression of IFN-γ was significantly decreased in Th cells. We also detected higher level of miR-21 in the ESCC patients which was significantly correlated with different subsets of Th cells. Our findings revealed that immune response related to the Th cells is highly impaired in ESCC patients. Association between miR-21 and Th subsets could be correlated with the impairment of anti-tumor immunity and ESCC pathogenesis, which could be potentially used as an important target for immunotherapeutic approaches.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Napier KJ, Scheerer M, Misra S. Esophageal cancer: a review of epidemiology, pathogenesis, staging workup and treatment modalities. World J Gastrointest Oncol. 2014;6(5):112–20.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Mosavi-Jarrahi A, Mohagheghi MA. Epidemiology of esophageal cancer in the high-risk population of Iran. Asian Pac J Cancer Prev. 2006;7(3):375–80.

    PubMed  Google Scholar 

  3. Kuai D-Y, Cheng J, Yang R-C, Liu T, Liu H, Liu F-G, et al. Th17/Treg cell imbalance in patients with early esophageal squamous cell carcinoma. Int J Clin Exp Pathol. 2016;9(8):8485–91.

    CAS  Google Scholar 

  4. Liang H, Fan J-H, Qiao Y-L. Epidemiology, etiology, and prevention of esophageal squamous cell carcinoma in China. Cancer Biol Med. 2017;14(1):33–41.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Jain S, Dhingra S. Pathology of esophageal cancer and Barrett’s esophagus. Ann Cardiothorac Surg. 2017;6(2):99–109.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Kono K, Kawaida H, Takahashi A, Sugai H, Mimura K, Miyagawa N, et al. CD4 (+) CD25high regulatory T cells increase with tumor stage in patients with gastric and esophageal cancers. Cancer Immunol Immunother. 2006;55(9):1064–71.

    Article  CAS  PubMed  Google Scholar 

  7. Fridman WH, Pagès F, Sautès-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12(4):298–306.

    Article  CAS  PubMed  Google Scholar 

  8. Dunn GP, Koebel CM, Schreiber RD. Interferons, immunity and cancer immunoediting. Nat Rev Immunol. 2006;6(11):836–48.

    Article  CAS  PubMed  Google Scholar 

  9. Kim H-J, Cantor H. CD4 T-cell subsets and tumor immunity: the helpful and the not-so-helpful. Cancer Immunol Res. 2014;2(2):91–8.

    Article  CAS  PubMed  Google Scholar 

  10. Guéry L, Hugues S. Th17 cell plasticity and functions in cancer immunity. Biomed Res Int. 2015;2015:1–11.

    Article  CAS  Google Scholar 

  11. Chen D, Jiang R, Mao C, Shi L, Wang S, Yu L, et al. Chemokine/chemokine receptor interactions contribute to the accumulation of Th17 cells in patients with esophageal squamous cell carcinoma. Hum Immunol. 2012;73(11):1068–72.

    Article  CAS  PubMed  Google Scholar 

  12. Chen D, Hu Q, Mao C, Jiao Z, Wang S, Yu L, et al. Increased IL-17-producing CD4+ T cells in patients with esophageal cancer. Cell Immunol. 2012;272(2):166–74.

    Article  CAS  PubMed  Google Scholar 

  13. Nagata J, Kijima H, Hatanaka H, Tokunaga T, Takagi A, Mine T, et al. Correlation between interleukin 10 and vascular endothelial growth factor expression in human esophageal cancer. Int J Mol Med. 2002;10(2):169–72.

    CAS  PubMed  Google Scholar 

  14. Lebman DA, Edmiston JS, Chung TD, Snyder SR. Heterogeneity in the transforming growth factor β response of esophageal cancer cells. Int J Oncol. 2002;20(6):1241–6.

    CAS  PubMed  Google Scholar 

  15. Song JH, Meltzer SJ. MicroRNAs in pathogenesis, diagnosis, and treatment of gastroesophageal cancers. Gastroenterology. 2012;143(1):35–47.

    Article  CAS  PubMed  Google Scholar 

  16. Zhou S-L, Wang L-D. Circulating microRNAs: novel biomarkers for esophageal cancer. World J Gastroenterol: WJG. 2010;16(19):2348–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Meng X, Lu P, Mei J, Liu G, Fan Q. Expression analysis of miRNA and target mRNAs in esophageal cancer. Braz J Med Biol Res. 2014;47(9):811–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hiyoshi Y, Kamohara H, Karashima R, Sato N, Imamura Y, Nagai Y, et al. MicroRNA-21 regulates the proliferation and invasion in esophageal squamous cell carcinoma. Clin Cancer Res. 2009;15(6):1915–22.

    Article  CAS  PubMed  Google Scholar 

  19. Steiner DF, Thomas MF, Hu JK, Yang Z, Babiarz JE, Allen CD, et al. MicroRNA-29 regulates T-box transcription factors and interferon-γ production in helper T cells. Immunity. 2011;35(2):169–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Zheng X, Dong L, Wang K, Zou H, Zhao S, Wang Y, et al. MiR-21 participates in the PD-1/PD-L1 pathway-mediated imbalance of Th17/Treg cells in patients after gastric Cancer resection. Ann Surg Oncol. 2019;26(3):884–93.

    Article  PubMed  Google Scholar 

  21. Yao R, Ma Y-L, Liang W, Li H-H, Ma Z-J, Yu X, et al. MicroRNA-155 modulates Treg and Th17 cells differentiation and Th17 cell function by targeting SOCS1. PLoS One. 2012;7(10):e46082.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sonkoly E, Janson P, Majuri M-L, Savinko T, Fyhrquist N, Eidsmo L, et al. MiR-155 is overexpressed in patients with atopic dermatitis and modulates T-cell proliferative responses by targeting cytotoxic T lymphocyte–associated antigen 4. J Allergy Clin Immunol. 2010;126(3):581–9.

  23. Banerjee A, Schambach F, DeJong CS, Hammond SM, Reiner SL. Micro-RNA-155 inhibits IFN-γ signaling in CD4+ T cells. Eur J Immunol. 2010;40(1):225–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wang P, Xu L-J, Qin J-J, Zhang L, Zhuang G-H. MicroRNA-155 inversely correlates with esophageal cancer progression through regulating tumor-associated macrophage FGF2 expression. Biochem Biophys Res Commun. 2018;503(2):452–8.

    Article  CAS  PubMed  Google Scholar 

  25. Ma H, Wen X, Zhang X, Wang X, Zhao D, Che S, et al. miR-106a* inhibits the proliferation of esophageal carcinoma cells by targeting CDK2-associated Cullin 1 (CACUL1). Cell Mol Biol (Noisy-le-Grand). 2015;61(4):56–62.

    CAS  Google Scholar 

  26. Sharma A, Kumar M, Aich J, Hariharan M, Brahmachari SK, Agrawal A, et al. Posttranscriptional regulation of interleukin-10 expression by hsa-miR-106a. Proc Natl Acad Sci. 2009;106(14):5761–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hong Z, Hong H, Liu J, Zheng X, Huang M, Li C, et al. miR-106a is downregulated in peripheral blood mononuclear cells of chronic hepatitis B and associated with enhanced levels of interleukin-8. Mediat Inflamm. 2015;2015:629862.

    Article  CAS  Google Scholar 

  28. Memarian A, Nourizadeh M, Masoumi F, Tabrizi M, Emami AH, Alimoghaddam K, et al. Upregulation of CD200 is associated with Foxp3+ regulatory T cell expansion and disease progression in acute myeloid leukemia. Tumor Biol. 2013;34(1):531–42.

    Article  CAS  Google Scholar 

  29. Baran J, Kowalczyk D, Oz M, Zembala M. Three-color flow cytometry detection of intracellular cytokines in peripheral blood mononuclear cells: comparative analysis of phorbol myristate acetate-ionomycin and phytohemagglutinin stimulation. Clin Diagn Lab Immunol. 2001;8(2):303–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Begenik H, Turkdogan MK, Dulger AC, Aldemir MN, Esen R, Mete R. Clinical immunology peripheral blood levels of cellular and humoral immunity parameters in esophageal and gastric cancer patients. Cent Eur J Immunol. 2013;38(3):355–7.

    Article  CAS  Google Scholar 

  31. Nana-Sinkam S, Croce C. Clinical applications for microRNAs in cancer. Clin Pharmacol Ther. 2013;93(1):98–104.

    Article  CAS  PubMed  Google Scholar 

  32. O'connell RM, Rao DS, Chaudhuri AA, Baltimore D. Physiological and pathological roles for microRNAs in the immune system. Nat Rev Immunol. 2010;10(2):111–22.

    Article  CAS  PubMed  Google Scholar 

  33. Blanck G. Components of the IFN-gamma signaling pathway in tumorigenesis. Arch Immunol Ther Exp. 2002;50(3):151–8.

    CAS  Google Scholar 

  34. Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol. 2004;22:329–60.

    Article  CAS  PubMed  Google Scholar 

  35. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol. 2002;3(11):991–8.

    Article  CAS  PubMed  Google Scholar 

  36. Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE, Old LJ, et al. IFNγ and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature. 2001;410(6832):1107–11.

    Article  CAS  PubMed  Google Scholar 

  37. Wang Y, Liu D, Chen P, Koeffler HP, Tong X, Xie D. Negative feedback regulation of IFN-γ pathway by IFN regulatory factor 2 in esophageal cancers. Cancer Res. 2008;68(4):1136–43.

    Article  CAS  PubMed  Google Scholar 

  38. Wang Y, Liu D-P, Chen P-P, Koeffler HP, Tong X-J, Xie D. Involvement of IFN regulatory factor (IRF)-1 and IRF-2 in the formation and progression of human esophageal cancers. Cancer Res. 2007;67(6):2535–43.

    Article  CAS  PubMed  Google Scholar 

  39. Murugaiyan G, Saha B. Protumor vs antitumor functions of IL-17. J Immunol. 2009;183(7):4169–75.

    Article  CAS  PubMed  Google Scholar 

  40. Lu L, Weng C, Mao H, Fang X, Liu X, Wu Y, et al. IL-17A promotes migration and tumor killing capability of B cells in esophageal squamous cell carcinoma. Oncotarget. 2016;7(16):21853–64.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Korn T, Oukka M, Kuchroo V, Bettelli E. Th17 cells: effector T cells with inflammatory properties. Semin Immunol. 2007;19(6):362–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Shi Y, Liu X-F, Zhuang Y, Zhang J-Y, Liu T, Yin Z, et al. Helicobacter pylori-induced Th17 responses modulate Th1 cell responses, benefit bacterial growth, and contribute to pathology in mice. J Immunol. 2010;184:5121–9.

    Article  CAS  PubMed  Google Scholar 

  43. Yoshimura A, Muto G. TGF-β function in immune suppression. Curr Top Microbiol Immunol. 2011;350:127–47.

    CAS  PubMed  Google Scholar 

  44. Joller N, Lozano E, Burkett PR, Patel B, Xiao S, Zhu C, et al. Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses. Immunity. 2014;40(4):569–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Xie J, Wang J, Cheng S, Zheng L, Ji F, Yang L, et al. Expression of immune checkpoints in T cells of esophageal cancer patients. Oncotarget. 2016;7(39):63669.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Gholamin M, Moaven O, Memar B, Farshchian M, Naseh H, Malekzadeh R, et al. Overexpression and interactions of interleukin-10, transforming growth factor β, and vascular endothelial growth factor in esophageal squamous cell carcinoma. World J Surg. 2009;33(7):1439–45.

    Article  PubMed  Google Scholar 

  47. Cao X. Regulatory T cells and immune tolerance to tumors. Immunol Res. 2010;46(1–3):79–93.

    Article  PubMed  Google Scholar 

  48. Grainger DJ, Mosedale DE, Metcalfe JC. TGF-β in blood: a complex problem. Cytokine Growth Factor Rev. 2000;11(1):133–45.

    Article  CAS  PubMed  Google Scholar 

  49. Winkler I, Wilczynska B, Bojarska-Junak A, Gogacz M, Adamiak A, Postawski K, et al. Regulatory T lymphocytes and transforming growth factor beta in epithelial ovarian tumors-prognostic significance. J Ovarian Res. 2015;8(1):39.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Sheen-Chen S-M, Chen H-S, Sheen C-W, Eng H-L, Chen W-J. Serum levels of transforming growth factor β1 in patients with breast cancer. Arch Surg. 2001;136(8):937–40.

    Article  CAS  PubMed  Google Scholar 

  51. Jarnicki AG, Lysaght J, Todryk S, Mills KH. Suppression of antitumor immunity by IL-10 and TGF-β-producing T cells infiltrating the growing tumor: influence of tumor environment on the induction of CD4+ and CD8+ regulatory T cells. J Immunol. 2006;177(2):896–904.

    Article  CAS  PubMed  Google Scholar 

  52. Del Prete G, De Carli M, Almerigogna F, Giudizi MG, Biagiotti R, Romagnani S. Human IL-10 is produced by both type 1 helper (Th1) and type 2 helper (Th2) T cell clones and inhibits their antigen-specific proliferation and cytokine production. J Immunol. 1993;150(2):353–60.

    PubMed  Google Scholar 

  53. Levings MK, Sangregorio R, Galbiati F, Squadrone S, de Waal Malefyt R, Roncarolo M-G. IFN-α and IL-10 induce the differentiation of human type 1 T regulatory cells. J Immunol. 2001;166(9):5530–9.

    Article  CAS  PubMed  Google Scholar 

  54. Kicielińska J, Pajtasz-Piasecka E. The role of IL-10 in the modulation of the immune response in normal conditions and the tumor environment. Postepy Hig Med Dosw (Online). 2014;68:879–92.

    Article  Google Scholar 

  55. Murugaiyan G, da Cunha AP, Ajay AK, Joller N, Garo LP, Kumaradevan S, et al. MicroRNA-21 promotes Th17 differentiation and mediates experimental autoimmune encephalomyelitis. J Clin Invest. 2015;125(3):1069–80.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Ugalde AP, Ramsay AJ, De La Rosa J, Varela I, Mariño G, Cadiñanos J, et al. Aging and chronic DNA damage response activate a regulatory pathway involving miR-29 and p53. EMBO J. 2011;30(11):2219–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Zhu Q, Wang Z, Hu Y, Li J, Li X, Zhou L, et al. miR-21 promotes migration and invasion by the miR-21-PDCD4-AP-1 feedback loop in human hepatocellular carcinoma. Oncol Rep. 2012;27(5):1660–8.

    CAS  PubMed  Google Scholar 

  58. Dong J, Zhao Y-P, Zhou L, Zhang T-P, Chen G. Bcl-2 upregulation induced by miR-21 via a direct interaction is associated with apoptosis and chemoresistance in MIA PaCa-2 pancreatic cancer cells. Arch Med Res. 2011;42(1):8–14.

    Article  CAS  PubMed  Google Scholar 

  59. Yan B, Guo Q, Fu F-j, Wang Z, Yin Z, Wei Y-b, et al. The role of miR-29b in cancer: regulation, function, and signaling. Onco Targets Ther. 2015;8:539–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Wei W, Wang Y, Yu X, Ye L, Jiang Y, Cheng Y. Expression of TP53, BCL-2, and VEGFA genes in esophagus carcinoma and its biological significance. Med Sci Monit. 2015;21:3016–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Qi Y, Li X, Zhao S. miR-29b inhibits the progression of esophageal squamous cell carcinoma by targeting MMP-2. Neoplasma. 2015;62(3):384–90.

    Article  CAS  PubMed  Google Scholar 

  62. Jiang H, Zhang G, Wu J-H, Jiang C-P. Diverse roles of miR-29 in cancer. Oncol Rep. 2014;31(4):1509–16.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This article was derived from a thesis of M.Sc. degree in the field of Immunology (Grant No. 978) at Semnan University of Medical Sciences, Semnan, Iran, in collaboration with Golestan University of Medical Sciences (Grant No. 950131021).

Author information

Authors and Affiliations

  1. Student Research Committee, Department of Immunology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran

    Hadiseh Samiei

  2. Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran

    Bizhan Sadighi-Moghaddam & Parviz Kokhaei

  3. Department of Immunology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran

    Bizhan Sadighi-Moghaddam

  4. Infectious Diseases Research Center, Golestan University of Medical Sciences, Gorgan, Iran

    Saeed Mohammadi

  5. Stem Cell Research center, Golestan University of Medical Sciences, Gorgan, Iran

    Saeed Mohammadi & Ayyoob Khosravi

  6. Digestive Oncology Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran

    Abdolsamad Gharavi

  7. Golestan Research Center of Gastroenterology and Hepatology, Golestan University of Medical Sciences, Gorgan, Iran

    Abdolsamad Gharavi & Ali Memarian

  8. Student Research Committee, Department of Immunology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran

    Sara Abdolmaleki

  9. Department of Molecular Medicine, School of Advanced Technologies in Medicine, Golestan University of Medical Sciences, Gorgan, Iran

    Ayyoob Khosravi & Hadi Bazzazi

  10. Immune and Gene Therapy Laboratory, Cancer Centre Karolinska, Department of Oncology and Pathology, Karolinska Institute, Stockholm, Sweden

    Parviz Kokhaei

  11. Department of Medical Laboratory Sciences, Gorgan Branch, Islamic Azad University, Gorgan, Iran

    Hadi Bazzazi

Authors
  1. Hadiseh Samiei
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bizhan Sadighi-Moghaddam
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Saeed Mohammadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Abdolsamad Gharavi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sara Abdolmaleki
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ayyoob Khosravi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Parviz Kokhaei
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hadi Bazzazi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ali Memarian
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ali Memarian.

Ethics declarations

Research involving human participants

The present study which involved human participants was approved by the ethical committee of Semnan University of Medical Sciences (Code of Ethics: IR.SEMUMS.REC.1394.215) and also Golestan University of Medical sciences (Code of Ethics: IR.GOUMS.REC.1395.28). A written informed consent following the declaration of Helsinki was taken from all participants.

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Samiei, H., Sadighi-Moghaddam, B., Mohammadi, S. et al. Dysregulation of helper T lymphocytes in esophageal squamous cell carcinoma (ESCC) patients is highly associated with aberrant production of miR-21. Immunol Res 67, 212–222 (2019). https://doi.org/10.1007/s12026-019-09079-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12026-019-09079-7

Keywords

Search

Navigation