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MiR-21 Participates in the PD-1/PD-L1 Pathway-Mediated Imbalance of Th17/Treg Cells in Patients After Gastric Cancer Resection

  • Translational Research and Biomarkers
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

The programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) pathway has been shown to be involved in trauma-induced immunosuppression and to influence CD4+ T cell differentiation. MicroRNA (miR)-21 is a critical player in immune responses. However, it remains largely unknown whether miR-21 is regulated by PD-1 and influences CD4+ T-cell lineage choice after gastric cancer resection.

Methods

In the present study, we analyzed the percentages of T-helper (Th)-17/regulatory T (Treg) cells and PD-1/PD-L1 expression on peripheral blood mononuclear cells (PBMCs) during the perioperative period. We also detected the secretion of interleukin (IL)-17 and transforming growth factor (TGF)-β1 using enzyme-linked immunosorbent assays (ELISAs). Furthermore, PBMCs isolated from patients were transfected with or without adenovirus-short hairpin-PD-1 (Ad-sh-PD1), pre-miR-21 or adenovirus–green fluorescent protein (Ad-GFP), and the percentages of Th17/Treg cells and related transcription factors were measured.

Results

In patients who underwent gastric cancer resection, the number of Th17 cells decreased, whereas the number of Treg cells increased, accompanied by an increased expression of PD-1/PD-L1. In addition, the expression of RORγt and IL-17 decreased, whereas the expression of Foxp3 and TGF-β1 increased. In vitro, silencing PD-1 via Ad-sh-PD1 promoted the expression of miR-21 and increased the percentage of Th17 cells, but decreased the percentage of Treg cells. The overexpression of miR-21 increased the percentage of Th17 cells but decreased the percentage of Treg cells.

Conclusions

Our study demonstrated that gastric cancer resection altered the balance of Th17/Treg cells and increased PD-1/PD-L1 expression. In the in vitro experiments, the transfection of Ad-sh-PD1 ameliorated Th17/Treg cell imbalance partially by increasing the expression of miR-21.

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References

  1. Hartgrink HH, Jansen EP, van Grieken NC, van de Velde CJ. Gastric cancer. Lancet. 2009;374:477–490.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Tohme S, Simmons RL, Tsung A. Surgery for cancer: a trigger for metastases. Cancer Res. 2017;77:1548–1552.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Marik PE, Flemmer M. The immune response to surgery and trauma: Implications for treatment. J Trauma Acute Care Surg. 2012;73:801–808.

    Article  CAS  PubMed  Google Scholar 

  4. Albertsmeier M, Quaiser D, von Dossow-Hanfstingl V, Winter H, Faist E, Angele MK. Major surgical trauma differentially affects t-cells and apc. Innate immunity. 2015;21:55–64.

    Article  CAS  PubMed  Google Scholar 

  5. Zamarron BF, Chen W. Dual roles of immune cells and their factors in cancer development and progression. Int J Biol Sci. 2011;7:651–658.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Glasner A, Avraham R, Rosenne E, et al. Improving survival rates in two models of spontaneous postoperative metastasis in mice by combined administration of a beta-adrenergic antagonist and a cyclooxygenase-2 inhibitor. J Immunol. 2010;184:2449–2457.

    Article  CAS  Google Scholar 

  7. Levi B, Benish M, Goldfarb Y, et al. Continuous stress disrupts immunostimulatory effects of il-12. Brain Behav Immun. 2011;25:727–735.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ostrand-Rosenberg S, Sinha P. Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol. 2009;182:4499–4506.

    Article  CAS  Google Scholar 

  9. Gottschalk A, Sharma S, Ford J, Durieux ME, Tiouririne M. Review article: the role of the perioperative period in recurrence after cancer surgery. Anesth. Analg. 2010;110:1636–1643.

    Article  PubMed  Google Scholar 

  10. Qadan M, Gardner SA, Vitale DS, Lominadze D, Joshua IG, Polk HC Jr. Hypothermia and surgery: immunologic mechanisms for current practice. Ann Surg. 2009;250:134–140.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Hogan BV, Peter MB, Shenoy HG, Horgan K, Hughes TA. Surgery induced immunosuppression. The Surgeon. 2011;9:38–43.

    Article  PubMed  Google Scholar 

  12. Al-Hasani R, Bruchas MR. Molecular mechanisms of opioid receptor-dependent signaling and behavior. Anesthesiology. 2011;115:1363–1381.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Stoecklein VM, Osuka A, Lederer JA. Trauma equals danger: damage control by the immune system. J Leukocyte Biol. 2012;92:539–551.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Matsuda A, Furukawa K, Suzuki H, et al. Does impaired th1/th2 balance cause postoperative infectious complications in colorectal cancer surgery? J Surg Res. 2007;139:15–21.

    Article  CAS  PubMed  Google Scholar 

  15. Zhu J, Paul WE. Peripheral CD4+T-cell differentiation regulated by networks of cytokines and transcription factors. Immunol Rev. 2010;238:247–262.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Yamane H, Paul WE. Early signaling events that underlie fate decisions of naive CD4(+) T cells toward distinct t-helper cell subsets. Immunol Rev. 2013;252:12–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Dai H, Sun T, Liu Z, Zhang J, Zhou M. The imbalance between regulatory and il-17-secreting CD4(+) T cells in multiple-trauma rat. Injury. 2013;44:1521–1527.

    Article  PubMed  Google Scholar 

  18. Spolarics Z, Siddiqi M, Siegel JH, et al. Depressed interleukin-12-producing activity by monocytes correlates with adverse clinical course and a shift toward th2-type lymphocyte pattern in severely injured male trauma patients. Critical Care Med. 2003;31:1722–1729.

    Article  CAS  PubMed  Google Scholar 

  19. Morishita K, Coimbra R, Langness S, Eliceiri BP, Costantini TW. Neuroenteric axis modulates the balance of regulatory T cells and T-helper 17 cells in the mesenteric lymph node following trauma/hemorrhagic shock. Am J Physiol Gastrointest Liver Physiol. 2015;309:G202–208.

  20. Watanabe R, Shirai T, Namkoong H, et al. Pyruvate controls the checkpoint inhibitor PD-L1 and suppresses T cell immunity. J Clin Invest. 2017;127:2725–2738.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Francisco LM, Salinas VH, Brown KE, et al. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med. 2009;206:3015–3029.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Dyck L, Wilk MM, Raverdeau M, Misiak A, Boon L, Mills KH. Anti-PD-1 inhibits foxp3+ treg cell conversion and unleashes intratumoural effector T cells thereby enhancing the efficacy of a cancer vaccine in a mouse model. Cancer Immunol Immunother. 2016;65:1491–1498.

    Article  CAS  PubMed  Google Scholar 

  23. Xu P, Zhang P, Sun Z, Wang Y, Chen J, Miao C. Surgical trauma induces postoperative t-cell dysfunction in lung cancer patients through the programmed death-1 pathway. Cancer Immunol Immunother. 2015;64:1383–1392.

    Article  CAS  PubMed  Google Scholar 

  24. Kinter AL, Godbout EJ, McNally JP, et al. The common gamma-chain cytokines il-2, il-7, il-15, and il-21 induce the expression of programmed death-1 and its ligands. J Immunol. 2008;181:6738–6746.

    Article  CAS  Google Scholar 

  25. Zhang Y, Shao Z, Zhang X, et al. Tipe2 play a negative role in tlr4-mediated autoimmune t helper 17 cell responses in patients with myasthenia gravis. J Neuroimmune Pharmacol. 2015;10:635–644.

    Article  PubMed  Google Scholar 

  26. Zhang Y, Li XF, Wu W, Chen Y. Dynamic changes of circulating t-helper cell subsets following severe thoracic trauma. Int J Clin Exp Med. 2015;8:21106–21113.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Gupta DL, Bhoi S, Mohan T, Galwnkar S, Rao DN. Coexistence of th1/th2 and th17/treg imbalances in patients with post traumatic sepsis. Cytokine. 2016;88:214–221.

    Article  CAS  PubMed  Google Scholar 

  28. Wu H, Wang K, Li G, et al. Effects of transcutaneous acupoint electrical stimulation on the imbalance of th1, th2, th17 and treg cells following thoracotomy of patients with lung cancer. Exp Ther Med. 2016;11:495–502.

    Article  CAS  PubMed  Google Scholar 

  29. Shen H, de Almeida PE, Kang KH, Yao P, Chan CW. Burn injury triggered dysfunction in dendritic cell response to tlr9 activation and resulted in skewed T cell functions. PloS One. 2012;7:e50238.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Dulos J, Carven GJ, van Boxtel SJ, et al. PD-1 blockade augments th1 and th17 and suppresses th2 responses in peripheral blood from patients with prostate and advanced melanoma cancer. J Immunother. 2012;35:169–178.

    Article  CAS  PubMed  Google Scholar 

  31. Arai Y, Saito H, Ikeguchi M. Upregulation of tim-3 and PD-1 on CD4 + and CD8 + T cells associated with dysfunction of cell-mediated immunity after colorectal cancer operation. Yonago Acta Medica. 2012;55:1–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Jiang XP, Huang XL, Yang ZP, et al. Iguratimod ameliorates inflammatory responses by modulating the th17/treg paradigm in dextran sulphate sodium-induced murine colitis. Mol Immunol. 2017;93:9–19.

    Article  CAS  PubMed  Google Scholar 

  33. Robertson SA, Zhang B, Chan H, et al. Microrna regulation of immune events at conception. Mol Reprod Dev. 2017;84:914–925.

    Article  CAS  PubMed  Google Scholar 

  34. Zhu J, Chen L, Zou L, et al. Mir-20b, -21, and -130b inhibit pten expression resulting in b7-h1 over-expression in advanced colorectal cancer. Hum Immunol. 2014;75:348–353.

    Article  CAS  PubMed  Google Scholar 

  35. Iliopoulos D, Kavousanaki M, Ioannou M, Boumpas D, Verginis P. The negative costimulatory molecule PD-1 modulates the balance between immunity and tolerance via mir-21. Eur J Immunol. 2011;41:1754–1763.

    Article  CAS  PubMed  Google Scholar 

  36. Hilliard A, Hilliard B, Zheng SJ, et al. Translational regulation of autoimmune inflammation and lymphoma genesis by programmed cell death 4. J Immunol. 2006;177:8095–8102.

    Article  CAS  Google Scholar 

Download references

Acknowledgment

This study was funded by the foundation of the National Natural Science Foundation of China (Grant No. 81571885), the Nn10 program of the Harbin Medical University Cancer Hospital and the Foundation of Heilongjiang Academy of Medical Sciences (Grant No. 201808).

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Authors and Affiliations

  1. Department of Anaesthesiology, Harbin Medical University Cancer Hospital, Harbin, China

    Xiaoyu Zheng MD, Linlin Dong MD, Kun Wang MD, Huichao Zou MD, Yu Wang MD & Guonian Wang MD, PhD

  2. Pain Research Institute of Heilongjiang Academy of Medical Sciences, Harbin, China

    Guonian Wang MD, PhD

  3. Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, Harbin, China

    Su Zhao MD

Authors
  1. Xiaoyu Zheng MD
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  2. Linlin Dong MD
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  3. Kun Wang MD
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  4. Huichao Zou MD
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  5. Su Zhao MD
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  6. Yu Wang MD
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  7. Guonian Wang MD, PhD
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Correspondence to Guonian Wang MD, PhD.

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Zheng, X., Dong, L., Wang, K. 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 26, 884–893 (2019). https://doi.org/10.1245/s10434-018-07117-6

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  • DOI: https://doi.org/10.1245/s10434-018-07117-6

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