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Effects of transarterial chemoembolization on regulatory T cell and its subpopulations in patients with hepatocellular carcinoma

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Abstract

Background

Regulatory T cell (Treg) plays an essential role in regulating anti-tumor immunity. The aim of this study was to investigate the effect of transarterial chemoembolization (TACE) on Treg in hepatocellular carcinoma (HCC) patients.

Method

The frequency of peripheral blood Tregs in 27 HCC patients who underwent TACE were measured at baseline and 1 month after TACE. The frequency of peripheral blood Tregs at baseline were compared with those in 23 healthy controls. Tregs were further classified into three subpopulations [Treg (I), Treg (II), Treg (III)] based on expression levels or markers and their function. The patients were divided into two groups according to tumor response after TACE; complete response group and incomplete response group. The correlations between the frequency of Treg and clinical factors were analyzed.

Results

The frequency of Treg in HCC patients (7.52%) was significantly higher than in healthy controls (4.99%) at baseline. Regarding Treg subpopulations, the frequency of Treg (II) was significantly higher in HCC patients (2.51%) than in healthy controls (0.60%). In comparison of Treg numbers at baseline and post-TACE by tumor response, the change of Treg (III) in complete response group from baseline to post-TACE was significantly decreased (63.8 → 53.2/mm3). Patients with a high post-TACE Treg (III) (3.8 months) exhibited a significantly shorter median time to progression than those with a low post-TACE Treg (III) (11.6 months). In multivariate analyses, hypoalbuminemia (hazard ratio 3.324; 95% CI 1.098–10.063, p = 0.034) and high post-TACE Treg (III) (hazard ratio 3.080; 95% CI 1.091–8.696, p = 0.034) were significant factors for associating with progression.

Conclusions

The frequency of Tregs in HCC patients was significantly higher than in healthy controls. In addition, patients with a high post-TACE Treg (III) exhibited a significantly lower progression-free survival rate than those with a low post-TACE Treg (III).

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Abbreviations

Treg:

Regulatory T cell

TACE:

Transarterial chemoembolization

HCC:

Hepatocellular carcinoma

HR:

Hazard ratio

CI:

Confidence interval

References

  1. Bruix J, Sala M, Llovet JM. Chemoembolization for hepatocellular carcinoma. Gastroenterology. 2004;127:S179–188.

    Article  CAS  Google Scholar 

  2. Jung MK, Shin EC. Regulatory T cells in hepatitis B and C virus infections. Immune Netw. 2016;16:330–6.

    Article  Google Scholar 

  3. Shin EC, Sung PS, Park SH. Immune responses and immunopathology in acute and chronic viral hepatitis. Nat Rev Immunol. 2016;16:509–23.

    Article  CAS  Google Scholar 

  4. Zhao DM, Thornton AM, DiPaolo RJ, Shevach EM. Activated CD4+CD25+ T cells selectively kill B lymphocytes. Blood. 2006;107:3925–32.

    Article  CAS  Google Scholar 

  5. Ghiringhelli F, Menard C, Martin F, Zitvogel L. The role of regulatory T cells in the control of natural killer cells: relevance during tumor progression. Immunol Rev. 2006;214:229–38.

    Article  CAS  Google Scholar 

  6. Mahnke K, Enk AH. Dendritic cells: key cells for the induction of regulatory T cells? Curr Top Microbiol Immunol. 2005;293:133–50.

    CAS  PubMed  Google Scholar 

  7. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol. 1995;155:1151–64.

    CAS  PubMed  Google Scholar 

  8. Miyara M, Yoshioka Y, Kitoh A, Shima T, Wing K, Niwa A, et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity. 2009;30:899–911.

    Article  CAS  Google Scholar 

  9. Wu CP, Qing X, Wu CY, Zhu H, Zhou HY. Immunophenotype and increased presence of CD4(+)CD25(+) regulatory T cells in patients with acute lymphoblastic leukemia. Oncol Lett. 2012;3:421–4.

    Article  CAS  Google Scholar 

  10. Liyanage UK, Moore TT, Joo HG, Tanaka Y, Herrmann V, Doherty G, et al. Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol. 2002;169:2756–61.

    Article  CAS  Google Scholar 

  11. Zhao E, Wang L, Dai J, Kryczek I, Wei S, Vatan L, et al. Regulatory T cells in the bone marrow microenvironment in patients with prostate cancer. Oncoimmunology. 2012;1:152–61.

    Article  CAS  Google Scholar 

  12. Badoual C, Hans S, Rodriguez J, Peyrard S, Klein C, Agueznay Nel H, et al. Prognostic value of tumor-infiltrating CD4+ T-cell subpopulations in head and neck cancers. Clin Cancer Res. 2006;12:465–72.

    Article  CAS  Google Scholar 

  13. Adurthi S, Mukherjee G, Krishnamurthy H, Sudhir K, Bafna UD, Umadevi K, et al. Functional tumor infiltrating TH1 and TH2 effectors in large early-stage cervical cancer are suppressed by regulatory T cells. Int J Gynecol Cancer. 2012;22:1130–7.

    Article  Google Scholar 

  14. Liao Y, Wang B, Huang ZL, Shi M, Yu XJ, Zheng L, et al. Increased circulating Th17 cells after transarterial chemoembolization correlate with improved survival in stage III hepatocellular carcinoma: a prospective study. PLoS ONE. 2013;8:e60444.

    Article  CAS  Google Scholar 

  15. Liao J, Xiao J, Zhou Y, Liu Z, Wang C. Effect of transcatheter arterial chemoembolization on cellular immune function and regulatory T cells in patients with hepatocellular carcinoma. Mol Med Rep. 2015;12:6065–71.

    Article  CAS  Google Scholar 

  16. Xiong B, Feng G, Luo S, Liang H, Qiu L, Zheng C, et al. Changes of CD4(+) CD25 (+) regulatory T cells in peripheral blood in patients with hepatocellular carcinoma before and after TACE. J Huazhong Univ Sci Technol Med Sci. 2008;28:645–8.

    Article  Google Scholar 

  17. Sun L, Xu G, Liao W, Yang H, Xu H, Du S, et al. Clinicopathologic and prognostic significance of regulatory T cells in patients with hepatocellular carcinoma: a meta-analysis. Oncotarget. 2017;8:39658–72.

    PubMed  PubMed Central  Google Scholar 

  18. Lee JH, Lee JH, Lim YS, Yeon JE, Song TJ, Yu SJ, et al. Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma. Gastroenterology. 2015;148(1383–1391):e1386.

    Google Scholar 

  19. Kudo M. Immuno-oncology in hepatocellular carcinoma: 2017 update. Oncology. 2017;93(Suppl 1):147–59.

    Article  Google Scholar 

  20. Xue TC, Jia QA, Ge NL, Chen Y, Zhang BH, Ye SL. Imbalance in systemic inflammation and immune response following transarterial chemoembolization potentially increases metastatic risk in huge hepatocellular carcinoma. Tumour Biol. 2015;36:8797–803.

    Article  CAS  Google Scholar 

  21. Tampaki M, Doumba PP, Deutsch M, Koskinas J. Circulating biomarkers of hepatocellular carcinoma response after locoregional treatments: new insights. World J Hepatol. 2015;7:1834–42.

    Article  Google Scholar 

  22. Korean Liver Cancer Study Group and National Cancer Center, Korea. Practice guidelines for management of hepatocellular carcinoma 2009. Korean J Hepatol. 2009;15:391–423. https://koreamed.org/article/1005KJHEP/2009.15.3.391

  23. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299:1057–61.

    Article  CAS  Google Scholar 

  24. Jiang D, Gao Z, Cai Z, Wang M, He J. Clinicopathological and prognostic significance of FOXP3+ tumor infiltrating lymphocytes in patients with breast cancer: a meta-analysis. BMC Cancer. 2015;15:727.

    Article  Google Scholar 

  25. Salama P, Phillips M, Grieu F, Morris M, Zeps N, Joseph D, et al. Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol. 2009;27:186–92.

    Article  Google Scholar 

  26. Curiel TJ. Regulatory T cells and treatment of cancer. Curr Opin Immunol. 2008;20:241–6.

    Article  CAS  Google Scholar 

  27. Frydrychowicz M, Boruczkowski M, Kolecka-Bednarczyk A, Dworacki G. The dual role of Treg in cancer. Scand J Immunol. 2017;86:436–43.

    Article  CAS  Google Scholar 

  28. Fu J, Xu D, Liu Z, Shi M, Zhao P, Fu B, et al. Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology. 2007;132:2328–39.

    Article  Google Scholar 

  29. Kobayashi N, Hiraoka N, Yamagami W, Ojima H, Kanai Y, Kosuge T, et al. FOXP3+ regulatory T cells affect the development and progression of hepatocarcinogenesis. Clin Cancer Res. 2007;13:902–11.

    Article  CAS  Google Scholar 

  30. Li F, Guo Z, Lizee G, Yu H, Wang H, Si T. Clinical prognostic value of CD4+CD25+FOXP3+regulatory T cells in peripheral blood of Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma patients. Clin Chem Lab Med. 2014;52:1357–65.

    CAS  PubMed  Google Scholar 

  31. Cao M, Cabrera R, Xu Y, Firpi R, Zhu H, Liu C, et al. Hepatocellular carcinoma cell supernatants increase expansion and function of CD4(+)CD25(+) regulatory T cells. Lab Investig. 2007;87:582–90.

    Article  CAS  Google Scholar 

  32. Menard C, Martin F, Apetoh L, Bouyer F, Ghiringhelli F. Cancer chemotherapy: not only a direct cytotoxic effect, but also an adjuvant for antitumor immunity. Cancer Immunol Immunother. 2008;57:1579–87.

    Article  CAS  Google Scholar 

  33. Sieghart W, Hucke F, Pinter M, Graziadei I, Vogel W, Muller C, et al. The ART of decision making: retreatment with transarterial chemoembolization in patients with hepatocellular carcinoma. Hepatology. 2013;57:2261–73.

    Article  CAS  Google Scholar 

  34. Zhang M, Zhou J, Zhao T, Huang G, Tan Y, Tan S, et al. Dissection of a circulating and intrahepatic CD4(+)Foxp3(+) T-cell subpopulation in chronic hepatitis B virus (HBV) infection: a highly informative strategy for distinguishing chronic HBV infection states. J Infect Dis. 2012;205:1111–20.

    Article  CAS  Google Scholar 

  35. Choi YS, Jung MK, Lee J, Choi SJ, Choi SH, Lee HW, et al. Tumor necrosis factor-producing T-regulatory cells are associated with severe liver injury in patients with acute hepatitis A. Gastroenterology. 2018;154:1047–60.

    Article  CAS  Google Scholar 

  36. Itoh Y, Okanoue T, Ohnishi N, Nishioji K, Sakamoto S, Nagao Y, et al. Hepatic damage induced by transcatheter arterial chemoembolization elevates serum concentrations of macrophage-colony stimulating factor. Liver. 1999;19:97–103.

    Article  CAS  Google Scholar 

  37. Wang Y, Zheng C, Liang B, Zhao H, Qian J, Liang H, et al. Hepatocellular necrosis, apoptosis, and proliferation after transcatheter arterial embolization or chemoembolization in a standardized rabbit model. J Vasc Interv Radiol. 2011;22:1606–12.

    Article  Google Scholar 

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Author notes

  1. Hana Park and Jae Hyung Jung have equally contributed to this work.

Authors and Affiliations

  1. Department of Internal Medicine, Yonsei Liver Center, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea

    Hana Park, Do Young Kim, Jun Yong Park & Kwang-Hyub Han

  2. Health Screening and Promotion Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea

    Hana Park

  3. Biomedical Science and Engineering Interdisciplinary Program, KAIST, Daejeon, Republic of Korea

    Jae Hyung Jung & Eui-Cheol Shin

  4. Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), 291, Daehak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea

    Min Kyung Jung & Eui-Cheol Shin

  5. Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea

    Simon Weonsang Ro, Do Young Kim, Jun Yong Park & Kwang-Hyub Han

  6. Department of Microbiology, Yonsei University College of Medicine, Seoul, Republic of Korea

    Jeon Han Park

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  1. Hana Park
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Correspondence to Min Kyung Jung or Kwang-Hyub Han.

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Conflict of interest

Hana Park, Jae Hyung Jung, Min Kyung Jung, Eui-Cheol Shin, Simon Weonsang Ro, Jeon Han Park, Do Young Kim, Jun Yong Park, Kwang-Hyub Han declare that they have no conflict of interest.

Informed consent

Patients gave written informed consent before joining the study, and the study protocol, approved by the Institutional Review Board of Severance Hospital, conformed to the ethical guidelines of the 1975 Declaration of Helsinki.

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Park, H., Jung, J.H., Jung, M.K. et al. Effects of transarterial chemoembolization on regulatory T cell and its subpopulations in patients with hepatocellular carcinoma. Hepatol Int 14, 249–258 (2020). https://doi.org/10.1007/s12072-020-10014-4

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  • DOI: https://doi.org/10.1007/s12072-020-10014-4

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