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Erschienen in: Hepatology International 2/2020

18.02.2020 | Original Article

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

verfasst von: 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

Erschienen in: Hepatology International | Ausgabe 2/2020

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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).
Literatur
1.
Zurück zum Zitat Bruix J, Sala M, Llovet JM. Chemoembolization for hepatocellular carcinoma. Gastroenterology. 2004;127:S179–188.CrossRef Bruix J, Sala M, Llovet JM. Chemoembolization for hepatocellular carcinoma. Gastroenterology. 2004;127:S179–188.CrossRef
2.
Zurück zum Zitat Jung MK, Shin EC. Regulatory T cells in hepatitis B and C virus infections. Immune Netw. 2016;16:330–6.CrossRef Jung MK, Shin EC. Regulatory T cells in hepatitis B and C virus infections. Immune Netw. 2016;16:330–6.CrossRef
3.
Zurück zum Zitat Shin EC, Sung PS, Park SH. Immune responses and immunopathology in acute and chronic viral hepatitis. Nat Rev Immunol. 2016;16:509–23.CrossRef Shin EC, Sung PS, Park SH. Immune responses and immunopathology in acute and chronic viral hepatitis. Nat Rev Immunol. 2016;16:509–23.CrossRef
4.
Zurück zum Zitat Zhao DM, Thornton AM, DiPaolo RJ, Shevach EM. Activated CD4+CD25+ T cells selectively kill B lymphocytes. Blood. 2006;107:3925–32.CrossRef Zhao DM, Thornton AM, DiPaolo RJ, Shevach EM. Activated CD4+CD25+ T cells selectively kill B lymphocytes. Blood. 2006;107:3925–32.CrossRef
5.
Zurück zum Zitat 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.CrossRef 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.CrossRef
6.
Zurück zum Zitat Mahnke K, Enk AH. Dendritic cells: key cells for the induction of regulatory T cells? Curr Top Microbiol Immunol. 2005;293:133–50.PubMed Mahnke K, Enk AH. Dendritic cells: key cells for the induction of regulatory T cells? Curr Top Microbiol Immunol. 2005;293:133–50.PubMed
7.
Zurück zum Zitat 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.PubMed 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.PubMed
8.
Zurück zum Zitat 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.CrossRef 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.CrossRef
9.
Zurück zum Zitat 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.CrossRef 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.CrossRef
10.
Zurück zum Zitat 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.CrossRef 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.CrossRef
11.
Zurück zum Zitat 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.CrossRef 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.CrossRef
12.
Zurück zum Zitat 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.CrossRef 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.CrossRef
13.
Zurück zum Zitat 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.CrossRef 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.CrossRef
14.
Zurück zum Zitat 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.CrossRef 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.CrossRef
15.
Zurück zum Zitat 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.CrossRef 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.CrossRef
16.
Zurück zum Zitat 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.CrossRef 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.CrossRef
17.
Zurück zum Zitat 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.PubMedPubMedCentral 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.PubMedPubMedCentral
18.
Zurück zum Zitat 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. 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.
19.
Zurück zum Zitat Kudo M. Immuno-oncology in hepatocellular carcinoma: 2017 update. Oncology. 2017;93(Suppl 1):147–59.CrossRef Kudo M. Immuno-oncology in hepatocellular carcinoma: 2017 update. Oncology. 2017;93(Suppl 1):147–59.CrossRef
20.
Zurück zum Zitat 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.CrossRef 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.CrossRef
21.
Zurück zum Zitat 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.CrossRef 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.CrossRef
23.
Zurück zum Zitat Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299:1057–61.CrossRef Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299:1057–61.CrossRef
24.
Zurück zum Zitat 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.CrossRef 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.CrossRef
25.
Zurück zum Zitat 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.CrossRef 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.CrossRef
26.
Zurück zum Zitat Curiel TJ. Regulatory T cells and treatment of cancer. Curr Opin Immunol. 2008;20:241–6.CrossRef Curiel TJ. Regulatory T cells and treatment of cancer. Curr Opin Immunol. 2008;20:241–6.CrossRef
27.
Zurück zum Zitat Frydrychowicz M, Boruczkowski M, Kolecka-Bednarczyk A, Dworacki G. The dual role of Treg in cancer. Scand J Immunol. 2017;86:436–43.CrossRef Frydrychowicz M, Boruczkowski M, Kolecka-Bednarczyk A, Dworacki G. The dual role of Treg in cancer. Scand J Immunol. 2017;86:436–43.CrossRef
28.
Zurück zum Zitat 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.CrossRef 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.CrossRef
29.
Zurück zum Zitat 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.CrossRef 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.CrossRef
30.
Zurück zum Zitat 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.PubMed 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.PubMed
31.
Zurück zum Zitat 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.CrossRef 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.CrossRef
32.
Zurück zum Zitat 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.CrossRef 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.CrossRef
33.
Zurück zum Zitat 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.CrossRef 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.CrossRef
34.
Zurück zum Zitat 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.CrossRef 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.CrossRef
35.
Zurück zum Zitat 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.CrossRef 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.CrossRef
36.
Zurück zum Zitat 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.CrossRef 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.CrossRef
37.
Zurück zum Zitat 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.CrossRef 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.CrossRef
Metadaten
Titel
Effects of transarterial chemoembolization on regulatory T cell and its subpopulations in patients with hepatocellular carcinoma
verfasst von
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
Publikationsdatum
18.02.2020
Verlag
Springer India
Erschienen in
Hepatology International / Ausgabe 2/2020
Print ISSN: 1936-0533
Elektronische ISSN: 1936-0541
DOI
https://doi.org/10.1007/s12072-020-10014-4

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