Association of preoperative EpCAM Circulating Tumor Cells and peripheral Treg cell levels with early recurrence of hepatocellular carcinoma following radical hepatic resection

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Abstract

Background

This study was carried out to determine the prognostic significance of preoperative peripheral epithelial cell adhesion molecule- positive ( EpCAM ⁺) circulating tumor cell (CTC) and T regulatory (Treg) cell levels in hepatocellular carcinoma (HCC) patients for the prediction of postoperative recurrence following curative resection.

Methods

A total of 49 patients about to undergo curative resection for HCC were recruited into the study. PCR and FACS were used to detect the preoperative levels of EpCAM ^mRNA+ CTCs and CD4 ⁺CD25 ⁺Foxp3 ⁺ Treg cells. The prognostic value of EpCAM ^mRNA+ CTCs, CD4 ⁺CD25 ⁺Foxp3 ⁺ Treg cells, and other clinicopathological factors were analyzed by applying the Kaplan–Meier method and the multivariate Cox proportional hazards model.

Results

The number of EpCAM ^mRNA+ CTCs and Treg/CD4 ⁺ cells showed significant correlation as prognostic factors of postoperative HCC recurrence: EpCAM ^mRNA+ CTC ≥ 2.22 (P = 0.001) and Treg/CD4 ⁺ ≥ 5.07 ( P = 0.045), with EpCAM ^mRNA+ CTC ≥ 2.22 ( P = 0.003, HR = 6.668) being the most important indicator. Patients with high CTC/Treg levels showed a significantly higher risk of developing postoperative HCC recurrence than those with low CTC/Treg levels (66.7 % vs. 10.3 %, P < 0.001). The high CTC/low Treg group also presented higher 1-year recurrence rates compared with the low CTC/low Treg level group (50.0 % vs. 10.3 %, P = 0.004).

Conclusions

Elevated EpCAM ^mRNA+ CTC and Treg/CD4 ⁺ levels were associated with early recurrence of HCC, indicative of poor clinical outcome. The combined detection of EpCAM ^mRNA+ CTC and Treg/CD4 ⁺ may therefore provide a novel prognostic predictor for HCC patients.

Electronic supplementary material

The online version of this article (doi:10.1186/s12885-016-2526-4) contains supplementary material, which is available to authorized users.

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Most cited references 17

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Management of hepatocellular carcinoma.

Jordi Bruix, Morris Sherman (2005)

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Regulatory T cells, tumour immunity and immunotherapy.

Weiping Zou (2006)

Tumours express a range of antigens, including self-antigens. Regulatory T cells are crucial for maintaining T-cell tolerance to self-antigens. Regulatory T cells are thought to dampen T-cell immunity to tumour-associated antigens and to be the main obstacle tempering successful immunotherapy and active vaccination. In this Review, I consider the nature and characteristics of regulatory T cells in the tumour microenvironment and their potential multiple suppressive mechanisms. Strategies for therapeutic targeting of regulatory T cells and the effect of regulatory T cells on current immunotherapeutic and vaccine regimens are discussed.

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Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection.

Qiang Gao, Shuang-Jian Qiu, Jia Fan … (2007)

To investigate the prognostic value of tumor-infiltrating lymphocytes (TILs), especially regulatory T cells (Tregs), in hepatocellular carcinoma (HCC) patients after resection. CD3+, CD4+, CD8+, Foxp3-positive, and granzyme B-positive TILs were assessed by immunohistochemistry in tissue microarrays containing HCC from 302 patients. Prognostic effects of low- or high-density TIL subsets were evaluated by Cox regression and Kaplan-Meier analysis using median values as cutoff. CD3+, CD4+, CD8+ TILs were associated with neither overall survival (OS) nor disease-free survival (DFS). The presence of low intratumoral Tregs in combination with high intratumoral activated CD8+ cytotoxic cells (CTLs), a balance toward CTLs, was an independent prognostic factor for both improved DFS (P = .001) and OS (P < .0001). Five-year OS and DFS rates were only 24.1% and 19.8% for the group with intratumoral high Tregs and low activated CTLs, compared with 64.0% and 59.4% for the group with intratumoral low Tregs and high activated CTLs, respectively. Either intratumoral Tregs alone (P = .001) or intratumoral activated CTLs (P = .001) alone is also an independent predictor for OS. In addition, high Tregs density was associated with both absence of tumor encapsulation (P = .032) and presence of tumor vascular invasion (P = .031). Tregs are associated with HCC invasiveness, and intratumoral balance of regulatory and cytotoxic T cells is a promising independent predictor for recurrence and survival in HCC. A combination of depletion of Tregs and concomitant stimulation of effector T cells may be an effective immunotherapy to reduce recurrence and prolong survival after surgery.

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Author and article information

Contributors

Yan Zhou: zhou.yan3@zs-hospital.sh.cn

Beili Wang: wang.beili1@zs-hospital.sh.cn

Jiong Wu: wu.jiong@zs-hospital.sh.cn

Chunyan Zhang: zhang.chunyan@zs-hospital.sh.cn

Yiwen Zhou: zhou.yiwen@zs-hospital.sh.cn

XinRong Yang: yang.xinrong@zs-hospital.sh.cn

Jian Zhou: zhou.jian@zs-hospital.sh.cn

Wei Guo: +86-21-64041990-2376 , guo.wei@zs-hospital.sh.cn

Jia Fan: +86-21-64037181 , fan.jia@zs-hospital.sh.cn

Journal

Journal ID (nlm-ta): BMC Cancer

Journal ID (iso-abbrev): BMC Cancer

Title: BMC Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2407

Publication date (Electronic): 20 July 2016

Publication date PMC-release: 20 July 2016

Publication date Collection: 2016

Volume: 16

Electronic Location Identifier: 506

Affiliations

[ ]Liver Cancer Institute, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032 People’s Republic of China

[ ]Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032 People’s Republic of China

Article

Publisher ID: 2526

DOI: 10.1186/s12885-016-2526-4

PMC ID: 4955266

PubMed ID: 27439521

SO-VID: 7af86495-46b2-46ed-a012-f078f5930f2f

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 26 September 2015

Date accepted : 6 July 2016

Funding

Funded by: the National High Technology Research and Development Program of CHINA

Award ID: 2015AA020401

Award Recipient : Jia Fan

Funded by: National Key Sci-Tech Project

Award ID: 2013ZX10002010-003& 2013ZX10002011-004)

Award Recipient : Jia Fan

Funded by: the National Natural Science Foundation of China

Award ID: 81572064

Award Recipient : Wei Guo

Funded by: FundRef http://dx.doi.org/10.13039/501100003399, Science and Technology Commission of Shanghai Municipality (CN);

Award ID: 14DZ1940300, 14DZ1940302,13140901900, 14411970200, 134119a1201 & 14140902301

Award Recipient : Jia Fan

Funded by: Specialized Research Fund for the Doctoral Program of Higher Education and Research Grants Council Earmarked Research Grants Joint Research Scheme

Award ID: 20130071140008

Award Recipient : Jia Fan

Funded by: the National Science & Technology Pillar Program

Award ID: 2012BAI37B01

Award Recipient : Wei Guo

Funded by: the National Nature Science Foundation of China

Award ID: 81530077, 81472676 & 81372317

Award Recipient : Jia Fan

Funded by: The funding plan for outstanding youth doctors training, Shanghai

Award ID: 2016-01

Award Recipient : Yan Zhou

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: hepatocellular carcinoma,tumor recurrence,circulating tumor cells,epithelial cell adhesion molecule,regulatory t cells

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: hepatocellular carcinoma, tumor recurrence, circulating tumor cells, epithelial cell adhesion molecule, regulatory t cells

Association of preoperative EpCAM Circulating Tumor Cells and peripheral Treg cell levels with early recurrence of hepatocellular carcinoma following radical hepatic resection

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Abstract

Background

Methods

Results

Conclusions

Electronic supplementary material

Related collections

Regulatory T cell (Treg) therapy

Most cited references 17

Management of hepatocellular carcinoma.

Regulatory T cells, tumour immunity and immunotherapy.

Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection.

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