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

  • Original Article
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Tumor Biology

Abstract

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.

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Abbreviations

CCRL1:

Chemokine receptor-like 1

HCC:

Hepatocellular carcinoma

RFA:

Radiofrequency ablation

ACR:

Atypical chemokine receptor

CCX-CKR:

ChemoCentryX chemokine receptor

TMA:

Tissue microarray

TTR:

Time to recurrence

OS:

Overall survival

IOD:

Integrated optical density

BCLC:

Barcelona clinic liver cancer

TNM:

Tumor-node-metastasis

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Acknowledgments

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).

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    Authors and Affiliations

    1. Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, People’s Republic of China

      Jie-Yi Shi, Meng Duan, Qi-Man Sun, Liuxiao Yang, Zhi-Chao Wang, Yi-Feng He, Jian Zhou, Jia Fan, Xiao-Ying Wang & Qiang Gao

    2. Department of ObGyn and Reproductive Medicine, Moscow State University of Medicine & Dentistry, Moscow, Russia

      Ospan A. Mynbaev

    3. Moscow Institute of Physics and Technology (State University), Moscow, Russia

      Ospan A. Mynbaev

    4. Biomedical Research Center, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China

      Ling-Yan Wang & Qiang Gao

    5. Institute of Biomedical Sciences, Fudan University, Shanghai, People’s Republic of China

      Jian Zhou & Jia Fan

    6. Key Laboratory of Molecular Medicine, the Ministry of Education, Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, People’s Republic of China

      Qi-Qun Tang

    7. Cancer Research Institute, Xiangya School of Medicine, Central South University, Hunan, China

      Ya Cao

    8. Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People’s Republic of China

      Xiao-Ying Wang & Qiang Gao

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    1. Jie-Yi Shi
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    Correspondence to Xiao-Ying Wang or Qiang Gao.

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

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    Additional information

    Jie-Yi Shi, Meng Duan and Qi-Man Sun contributed equally to this work.

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    Shi, JY., Duan, M., Sun, QM. et al. Naive Treg-like CCR7+ mononuclear cells indicate unfavorable prognosis in hepatocellular carcinoma. Tumor Biol. 37, 9909–9917 (2016). https://doi.org/10.1007/s13277-015-4647-9

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    • DOI: https://doi.org/10.1007/s13277-015-4647-9

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