Clinical prognostic value of CD4+CD25+FOXP3+regulatory T cells in peripheral blood of Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma patients
-
Fenge Li
,
Gregory Lizée
Abstract
Background: CD4+CD25+ forkhead box P3 (FOXP3)+ regulatory T cells (Tregs) accumulate in malignant tumors and negatively regulate antitumor immunity. However, the clinical significance of Tregs in HCC remains unclear. To determine the prognostic value of Tregs, we conducted a retrospective study on 264 patients with Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma (HCC) who underwent transcatheter arterial chemoembolization (TACE).
Methods: We measured the proportion of peripheral blood Tregs in 105 healthy donors and 264 HCC patients (stage B) prior to and following TACE between 2005 and 2007. All HCC patients were followed up until December 2012. The correlations between the proportion of Tregs and clinicopathologic factors were analyzed, and long-term survival rate after TACE according to the percentage of Tregs was assessed by univariate and multivariate analyses.
Results: The 1-, 2-, 3-, 4- and 5-year cumulative survival rates were 62.1%, 32.6%, 16.5%, 10.4% and 6.9%, respectively, and the median survival time was 19.0 months. The cumulative survival rate was significantly lower in patients with higher levels of peripheral blood Treg cells compared to those with lower Treg levels (p<0.001). Furthermore, we found that both pre- and post-TACE peripheral blood Treg levels showed significant negative association with overall survival time (p<0.001).
Conclusions: Elevated peripheral blood CD4+CD25+FOXP3+Treg levels are an independent predictive factor of poor survival after TACE for HCC (stage B) patients. These results suggest that targeting Tregs may improve patient outcomes, and provide a strong rationale for testing these approaches in future immunotherapy-based clinical trials.
Acknowledgments
Thanks to Dr. Xingding Zhang and Patricia Fox of the University of Texas M.D. Anderson Cancer Center for statistical advice. This work was supported in part by the National Natural Science Foundation of China (No. 81001002, 30973438, 81101754), Tianjin Natural Science Foundation (No. 09JCYBJC10400), Tianjin Health Bureau Foundation (No. 2010KZ7, 2011KZ74) and Tianjin Medical University Science Foundation (No.2011KY14).
Conflict of interest statement
Authors’ conflict of interest disclosure: The authors stated that there are no conflicts of interest regarding the publication of this article. Research support played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
References
1. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003;362:1907–17.10.1016/S0140-6736(03)14964-1Search in Google Scholar
2. El-Serag HB, Marrero JA, Rudolph L, Reddy KR. Diagnosis and treatment of hepatocellular carcinoma. Gastroenterology 2008;134:1752–63.10.1053/j.gastro.2008.02.090Search in Google Scholar PubMed
3. Bruix J, Llovet JM. Prognostic prediction and treatment strategy in hepatocellular carcinoma. Hepatology 2002;35:519–24.10.1053/jhep.2002.32089Search in Google Scholar PubMed
4. Bruix J, Sala M, Llovet JM. Chemoembolization for hepatocellular carcinoma. Gastroenterology 2004;127:S179–88.10.1053/j.gastro.2004.09.032Search in Google Scholar PubMed
5. Greten TF, Jaffee EM. Cancer vaccines. J Clin Oncol 1999;17: 1047–60.10.1200/JCO.1999.17.3.1047Search in Google Scholar PubMed
6. Ladhams A, Schmidt C, Sing G, Butterworth L, Fielding G, Tesar P, et al. Treatment of non-resectable hepatocellular carcinoma with autologous tumor-pulsed dendritic cells. J Gastroenterol Hepatol 2002;17:889–96.10.1046/j.1440-1746.2002.02817.xSearch in Google Scholar PubMed
7. Korangy F, Ormandy LA, Bleck JS, Klempnauer J, Wilkens L, Manns MP, et al. Spontaneous tumor specific humoral and cellular immune responses to NY-ESO-1 in hepatocellular carcinoma. Clin Cancer Res 2004;10:4332–41.10.1158/1078-0432.CCR-04-0181Search in Google Scholar PubMed
8. 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;155:1151–64.10.4049/jimmunol.155.3.1151Search in Google Scholar
9. Von Boehmer H. Mechanisms of suppression by suppressor T cells. Nat Immunol 2005;6:338–44.10.1038/ni1180Search in Google Scholar PubMed
10. Fontenot JD, Rudensky AY. A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3. Nat Immunol 2005;6:331–7.10.1038/ni1179Search in Google Scholar PubMed
11. Chen ML, Pittet MJ, Gorelik L, Flavell RA, Weissleder R, von Boehmer H, et al. Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-β signals in vivo. Proc Natl Acad Sci USA 2005;102:419–24.10.1073/pnas.0408197102Search in Google Scholar PubMed PubMed Central
12. Nishikawa H, Kato T, Tawara I, Takemitsu T, Saito K, Wang L, et al. Accelerated chemically induced tumor development mediated by CD4+CD25+ regulatory T cells in wild-type hosts. Proc Natl Acad Sci USA 2005;102:9253–7.10.1073/pnas.0503852102Search in Google Scholar PubMed PubMed Central
13. Chen X, Du Y, Huang Z. CD4+CD25+ Treg derived from hepatocellular carcinoma mice inhibit tumor immunity. Immunol Lett 2012;148:83–9.10.1016/j.imlet.2012.09.002Search in Google Scholar PubMed
14. 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;3:421–4.10.3892/ol.2011.499Search in Google Scholar PubMed PubMed Central
15. 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;169:2756–61.10.4049/jimmunol.169.5.2756Search in Google Scholar PubMed
16. 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;1:152–61.10.4161/onci.1.2.18480Search in Google Scholar PubMed PubMed Central
17. 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;12:465–72.10.1158/1078-0432.CCR-05-1886Search in Google Scholar PubMed
18. 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;22:1130–7.10.1097/IGC.0b013e318262aa53Search in Google Scholar PubMed
19. Unitt E, Rushbrook SM, Marshall A, Davies S, Gibbs P, Morris LS, et al. Compromised lymphocytes infiltrate hepatocellular carcinoma: the role of T regulatory cells. Hepatology 2005;41: 722–30.10.1002/hep.20644Search in Google Scholar PubMed
20. Yang XH, Yamagiwa S, Ichida T, Matsuda Y, Sugahara S, Watanabe H, et al. Increase of CD4+CD25+regulatory T cells in the liver of patients with hepatocellular carcinoma. J Hepatol 2006;45:254–62.10.1016/j.jhep.2006.01.036Search in Google Scholar PubMed
21. Feng X, Li B, Ye H, Long D. Increased frequency of CD4+CD25(high)FoxP3+ regulatory T cells in patients with hepatocellular carcinoma. Arch Immunol Ther Exp 2011;59: 309–14.10.1007/s00005-011-0127-0Search in Google Scholar PubMed
22. Kobayshi N, Hiraoka N, Yamagami W, Ojima H, Kanai Y, Kosuge T, et al. FOXP3+regulatory T cells affect development and progression of hepatocarcinogenesis. Clin Cancer Res 2007;13:902–11.10.1158/1078-0432.CCR-06-2363Search in Google Scholar PubMed
23. Sasaki A, Tanaka F, Mimori K, Inoue H, Kai S, Shibata K, et al. Prognostic value of tumor-infiltrating FOXP3+regulatory T cells in patients with hepatocellular carcinoma. Eur J Surg Oncol 2008;34:173–9.10.1016/j.ejso.2007.08.008Search in Google Scholar PubMed
24. Ormandy LA, Hillemann T, Wedemeyer H, Manns MP, Greten TF, Korangy F. Increased populations of regulatory T cells in peripheral blood of patients with hepatocellular carcinoma. Cancer Res 2005;65:2457–64.10.1158/0008-5472.CAN-04-3232Search in Google Scholar PubMed
25. Yoshizawa K, Abe H, Kubo Y, Kitahara T, Aizawa R, Matsuoka M, et al. Expansion of CD4(+)CD25(+)FoxP3(+) regulatory T cells in hepatitis C virus-related chronic hepatitis, cirrhosis and hepatocellular carcinoma. Hepatol Res 2010;40:179–87.10.1111/j.1872-034X.2009.00587.xSearch in Google Scholar PubMed
26. Gaur P, Qadir GA, Upadhyay S, Singh AK, Shukla NK, Das SN. Skewed immunological balance between Th17 (CD4+IL17A+) and Treg (CD4+CD25+FOXP3+) cells in human oral squamous cell carcinoma. Cell Oncol (Dordr) 2012;35:335–43.10.1007/s13402-012-0093-5Search in Google Scholar PubMed
27. Feyler S, von Lilienfeld-Toal M, Jarmin S, Marles L, Rawstron A, Ashcroft AJ, et al. CD4(+)CD25(+)FoxP3(+) regulatory T cells are increased whilst CD3(+)CD4(-)CD8(-)alphabetaTCR(+) Double Negative T cells are decreased in the peripheral blood of patients with multiple myeloma which correlates with disease burden. Br J Haematol 2009;144:686–95.10.1111/j.1365-2141.2008.07530.xSearch in Google Scholar PubMed
28. Takahashi T, Kuniyasu Y, Toda M, Sakaguchi N, Itoh M, Iwata M, et al. Immunologic self-tolerance maintained by CD25+CD4+naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state. Int Immunol 1998;10:1969–80.10.1093/intimm/10.12.1969Search in Google Scholar PubMed
29. Yoshiko T, Yasunari N, Akiko N, Terashima T, Arihara F, Kitahara M, et al. Frequency of CD45RO+subset in CD4+CD25highregulatory T cells associated with progression of hepatocellular carcinoma. Cancer Letters 2011;307:165–73.10.1016/j.canlet.2011.03.029Search in Google Scholar PubMed
30. Sakaguchi S, Sakaguchi N, Shimizu J, Yamazaki S, Sakihama T, Itoh M, et al. Immunologic tolerance maintained by CD25+CD4+regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol Rev 2001;182:18–32.10.1034/j.1600-065X.2001.1820102.xSearch in Google Scholar PubMed
31. Nishikawa H, Sakaguchi S. Regulatory T cells in tumor immunity. Int J Cancer 2010;127:759–67.10.1002/ijc.25429Search in Google Scholar PubMed
32. Frey DM, Droeser RA, Viehl CT, Zlobec I, Lugli A, Zingg U, et al. High frequency of tumor-infiltrating FOXP3(+)regulatory T cells predicts improved survival in mismatch repair-proficient colorectal cancer patients. Int J Cancer 2010;126:2635–43.10.1002/ijc.24989Search in Google Scholar PubMed
33. Shen X, Li N, Li H, Zhang T, Wang F, Li Q. Increased prevalence of regulatory T cells in the tumor microenvironment and its correlation with TNM stage of hepatocellular carcinoma. J Cancer Res Clin Oncol 2010;136:1745–54.10.1007/s00432-010-0833-8Search in Google Scholar PubMed
34. Zhou J, Ding T, Pan W, Zhu LY, Li L, Zheng L. Increased intra-tumoral regulatory T cells are related to intratumoral macrophages and poor prognosis in hepatocellular carcinoma patients. Int J Cancer 2009;125:1640–8.10.1002/ijc.24556Search in Google Scholar PubMed
35. Huang Y, Wang FM, Wang T, Wang YJ, Zhu ZY, Gao YT, et al. Tumor-infiltrating FoxP3+ Tregs and CD8+ T cells affect the prognosis of hepatocellular carcinoma patients. Digestion 2012;86:329–37.10.1159/000342801Search in Google Scholar PubMed
36. Liu F, Lang R, Zhao J, Zhang X, Pringle GA, Fan Y, et al. CD8+ cytotoxic T cell and FOXP3+ regulatory T cell infiltration in relation to breast cancer survival and molecular subtypes. Breast Cancer Res Treat 2011;130:645–55.10.1007/s10549-011-1647-3Search in Google Scholar PubMed
37. Dercamp C, Chemin K, Caux C, Trinchieri G, Vicari AP. Distinct and overlapping roles of interleukin-10 and CD25 þ regulatory T cells in the inhibition of antitumor CD8 T-cell responses. Cancer Res 2005;65:8479–86.10.1158/0008-5472.CAN-05-1319Search in Google Scholar PubMed
38. Schmidt A, Oberle N, Krammer PH. Molecular mechanisms of Treg-mediated T cell suppression. Front Immunol 2012;3:51.10.3389/fimmu.2012.00051Search in Google Scholar PubMed PubMed Central
39. Suvas S, Kumaraguru U, Pack CD, Lee S, Rouse BT. CD4+CD25+T cells regulate virus-specific primary and memory CD8 +T cell responses. J Exp Med 2003;198:889–901.10.1084/jem.20030171Search in Google Scholar PubMed PubMed Central
©2014 by De Gruyter
Articles in the same Issue
- Frontmatter
- Editorial
- Red blood cell distribution width (RDW) and human pathology. One size fits all
- Reviews
- LC-MS candidate reference methods for the harmonisation of parathyroid hormone (PTH) measurement: a review of recent developments and future considerations
- C-reactive protein and migraine. Facts or speculations?
- Mini Review
- ABO blood group and von Willebrand factor: biological implications
- Genetics and Molecular Diagnostics
- Lactase persistence genotyping: rapid detection of seven sequence variants in a single tube with melting curve analyses
- General Clinical Chemistry and Laboratory Medicine
- The 3rd International Standard for serum IgE: international collaborative study to evaluate a candidate preparation
- Improving CardioCheck PA analytical performance: three-year study
- Serum copeptin level predicts a rapid decrease of overhydration after kidney transplantation
- Thyroid function and thyroid autoimmunity in apparently healthy pregnant and non-pregnant Mexican women
- Serum and follicular fluid fetuin-A in women undergoing in vitro fertilization
- Value of reelin for assessing hepatic fibrogenesis in a group of Egyptian HCV infected patients
- IgA anticardiolipin and IgA anti-β2 glycoprotein I antibody positivity determined by fluorescence enzyme immunoassay in primary antiphospholipid syndrome
- Reference Values and Biological Variations
- Serum glucose adjusted cut-off values for normal cerebrospinal fluid/serum glucose ratio: implications for clinical practice
- Age- and gender-specific brain natriuretic peptide (BNP) reference ranges in primary care
- Cancer Diagnostics
- Clinical utility of %p2PSA and prostate health index in the detection of prostate cancer
- Clinical prognostic value of CD4+CD25+FOXP3+regulatory T cells in peripheral blood of Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma patients
- Increased expression of carbonic anhydrase IX in oral submucous fibrosis and oral squamous cell carcinoma
- Cardiovascular Diseases
- Ideal cardiovascular health behaviors and factors and high sensitivity C-reactive protein: the Kailuan cross-sectional study in Chinese
- Letters to the Editor
- Red cell distribution width predicts chronic thromboembolic pulmonary hypertension in patients with acute pulmonary embolism in a long-term follow-up
- Red blood cell distribution width is significantly associated with aging and gender
- Red blood cell distribution width: a potential prognostic index for liver disease?
- Serum folate and vitamin B12: does light really matter?
- Thalassemia diagnosis in a blood donor from a unique trimorphic red blood cell population observed in the recipient
- A preliminary study on serum proteomics in fibromyalgia syndrome
- First study of angiotensin converting enzyme in cystic fibrosis Tunisian patients
- FlashFISH™: a novel technique for rapid diagnosis of aneuploidies in dysmorphic neonates
- Determination of the amniotic fluid lecithin/sphingomyelin ratio using a pipette tip column with a cation-exchange resin and mass spectrometry
- Congress Abstracts
- 57th National Congress of the Hungarian Society of Laboratory Medicine
Articles in the same Issue
- Frontmatter
- Editorial
- Red blood cell distribution width (RDW) and human pathology. One size fits all
- Reviews
- LC-MS candidate reference methods for the harmonisation of parathyroid hormone (PTH) measurement: a review of recent developments and future considerations
- C-reactive protein and migraine. Facts or speculations?
- Mini Review
- ABO blood group and von Willebrand factor: biological implications
- Genetics and Molecular Diagnostics
- Lactase persistence genotyping: rapid detection of seven sequence variants in a single tube with melting curve analyses
- General Clinical Chemistry and Laboratory Medicine
- The 3rd International Standard for serum IgE: international collaborative study to evaluate a candidate preparation
- Improving CardioCheck PA analytical performance: three-year study
- Serum copeptin level predicts a rapid decrease of overhydration after kidney transplantation
- Thyroid function and thyroid autoimmunity in apparently healthy pregnant and non-pregnant Mexican women
- Serum and follicular fluid fetuin-A in women undergoing in vitro fertilization
- Value of reelin for assessing hepatic fibrogenesis in a group of Egyptian HCV infected patients
- IgA anticardiolipin and IgA anti-β2 glycoprotein I antibody positivity determined by fluorescence enzyme immunoassay in primary antiphospholipid syndrome
- Reference Values and Biological Variations
- Serum glucose adjusted cut-off values for normal cerebrospinal fluid/serum glucose ratio: implications for clinical practice
- Age- and gender-specific brain natriuretic peptide (BNP) reference ranges in primary care
- Cancer Diagnostics
- Clinical utility of %p2PSA and prostate health index in the detection of prostate cancer
- Clinical prognostic value of CD4+CD25+FOXP3+regulatory T cells in peripheral blood of Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma patients
- Increased expression of carbonic anhydrase IX in oral submucous fibrosis and oral squamous cell carcinoma
- Cardiovascular Diseases
- Ideal cardiovascular health behaviors and factors and high sensitivity C-reactive protein: the Kailuan cross-sectional study in Chinese
- Letters to the Editor
- Red cell distribution width predicts chronic thromboembolic pulmonary hypertension in patients with acute pulmonary embolism in a long-term follow-up
- Red blood cell distribution width is significantly associated with aging and gender
- Red blood cell distribution width: a potential prognostic index for liver disease?
- Serum folate and vitamin B12: does light really matter?
- Thalassemia diagnosis in a blood donor from a unique trimorphic red blood cell population observed in the recipient
- A preliminary study on serum proteomics in fibromyalgia syndrome
- First study of angiotensin converting enzyme in cystic fibrosis Tunisian patients
- FlashFISH™: a novel technique for rapid diagnosis of aneuploidies in dysmorphic neonates
- Determination of the amniotic fluid lecithin/sphingomyelin ratio using a pipette tip column with a cation-exchange resin and mass spectrometry
- Congress Abstracts
- 57th National Congress of the Hungarian Society of Laboratory Medicine
