Tumor Biology

, Volume 37, Issue 7, pp 9909–9917 | Cite as

Naive Treg-like CCR7+ mononuclear cells indicate unfavorable prognosis in hepatocellular carcinoma

  • Jie-Yi Shi
  • Meng Duan
  • Qi-Man Sun
  • Liuxiao Yang
  • Zhi-Chao Wang
  • Ospan A. Mynbaev
  • Yi-Feng He
  • Ling-Yan Wang
  • Jian Zhou
  • Qi-Qun Tang
  • Ya Cao
  • Jia Fan
  • Xiao-Ying WangEmail author
  • Qiang GaoEmail author
Original Article


Chemokine receptor-like 1 (CCRL1) has the potential in creating a low level of CCL19 and CCL21 to hinder CCR7+ cell tracking to tumor tissue. Previously, we found a tumor suppressive role of CCRL1 by impairing CCR7-related chemotaxis of tumor cells in human hepatocellular carcinoma (HCC). Here, we reported a contribution of CCR7+ mononuclear cells in the tumor microenvironment to the progression of disease. Immunohistochemistry was used to investigate the distribution and clinical significance of CCR7+ cells in a cohort of 240 HCC patients. Furthermore, the phenotype, composition, and functional status of CCR7+ cells were determined by flow cytometry, immunofluorescence, and in vitro co-culture assays. We found that CCR7+ mononuclear cells were dispersed around tumor tissue and negatively related to tumoral expression of CCRL1 (P < 0.001, r = 0.391). High density of CCR7+ mononuclear cells positively correlated with the absence of tumor capsule, vascular invasion, and poor differentiation (P < 0.05). Survival analyses revealed that increased number of CCR7+ mononuclear cells was significantly associated with worse survival and increased recurrence. We found that CCR7+ mononuclear cells featured a naive Treg-like phenotype (CD45RA+CD25+FOXP3+) and possessed tumor-promoting potential by producing TGF-β1. Moreover, CCR7+ cells were also composed of several immunocytes, a third of which were CD8+ T cells. CCR7+ Treg-like cells facilitate tumor growth and indicate unfavorable prognosis in HCC patients, but fortunately, their tracking to tumor tissue is under the control of CCRL1.


CCR7 CCRL1 Treg-like Tumor microenvironment 



Chemokine receptor-like 1


Hepatocellular carcinoma


Radiofrequency ablation


Atypical chemokine receptor


ChemoCentryX chemokine receptor


Tissue microarray


Time to recurrence


Overall survival


Integrated optical density


Barcelona clinic liver cancer





This work was supported by the National Key Sci-Tech Project (2012ZX10002011-002), National Natural Science Foundation of China (81401928, 81272730, and 81101805), FANEDD (No. 201183), Shanghai “Promising Youth Medical Worker” Project (No. 13Y055), and Shanghai Health Bureau Scientific Research Found Projects (No. 2009Y007).

Compliance with ethical standards

Study was conducted according to the ethical approval from Zhongshan Hospital Research Ethics Committee and after obtaining written consents from patients.

Conflicts of interest


Supplementary material

13277_2015_4647_MOESM1_ESM.docx (33 kb)
Supplemental Table S1 (DOCX 33 kb)
13277_2015_4647_MOESM2_ESM.docx (33 kb)
Supplemental Table S2 (DOCX 32 kb)


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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Jie-Yi Shi
    • 1
  • Meng Duan
    • 1
  • Qi-Man Sun
    • 1
  • Liuxiao Yang
    • 1
  • Zhi-Chao Wang
    • 1
  • Ospan A. Mynbaev
    • 2
    • 3
  • Yi-Feng He
    • 1
  • Ling-Yan Wang
    • 4
  • Jian Zhou
    • 1
    • 5
  • Qi-Qun Tang
    • 6
  • Ya Cao
    • 7
  • Jia Fan
    • 1
    • 5
  • Xiao-Ying Wang
    • 1
    • 8
    Email author
  • Qiang Gao
    • 1
    • 4
    • 8
    Email author
  1. 1.Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education)Fudan UniversityShanghaiPeople’s Republic of China
  2. 2.Department of ObGyn and Reproductive MedicineMoscow State University of Medicine & DentistryMoscowRussia
  3. 3.Moscow Institute of Physics and Technology (State University)MoscowRussia
  4. 4.Biomedical Research Center, Zhongshan HospitalFudan UniversityShanghaiPeople’s Republic of China
  5. 5.Institute of Biomedical SciencesFudan UniversityShanghaiPeople’s Republic of China
  6. 6.Key Laboratory of Molecular Medicine, the Ministry of Education, Department of Biochemistry and Molecular BiologyFudan University Shanghai Medical CollegeShanghaiPeople’s Republic of China
  7. 7.Cancer Research Institute, Xiangya School of MedicineCentral South UniversityHunanChina
  8. 8.Liver Cancer Institute, Zhongshan HospitalFudan UniversityShanghaiPeople’s Republic of China

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