title: Naive Treg-like CCR7(+) mononuclear cells indicate unfavorable prognosis in hepatocellular carcinoma.
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.
authors.affiliation: Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, People's Republic of China.
authors.forename: Jie-Yi
authors.initials: JY
authors.lastname: Shi
authors.affiliation: Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, People's Republic of China.
authors.forename: Meng
authors.initials: M
authors.lastname: Duan
authors.affiliation: Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, People's Republic of China.
authors.forename: Qi-Man
authors.initials: QM
authors.lastname: Sun
authors.affiliation: Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, People's Republic of China.
authors.forename: Liuxiao
authors.initials: L
authors.lastname: Yang
authors.affiliation: Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, People's Republic of China.
authors.forename: Zhi-Chao
authors.initials: ZC
authors.lastname: Wang
authors.affiliation: Department of ObGyn and Reproductive Medicine, Moscow State University of Medicine & Dentistry, Moscow, Russia.|Moscow Institute of Physics and Technology (State University), Moscow, Russia.
authors.forename: Ospan A
authors.initials: OA
authors.lastname: Mynbaev
authors.affiliation: Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, People's Republic of China.
authors.forename: Yi-Feng
authors.initials: YF
authors.lastname: He
authors.affiliation: Biomedical Research Center, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China.
authors.forename: Ling-Yan
authors.initials: LY
authors.lastname: Wang
authors.affiliation: Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, People's Republic of China.|Institute of Biomedical Sciences, Fudan University, Shanghai, People's Republic of China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: Qi-Qun
authors.initials: QQ
authors.lastname: Tang
authors.affiliation: Cancer Research Institute, Xiangya School of Medicine, Central South University, Hunan, China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, People's Republic of China.|Institute of Biomedical Sciences, Fudan University, Shanghai, People's Republic of China.
authors.forename: Jia
authors.initials: J
authors.lastname: Fan
authors.affiliation: Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, People's Republic of China. xiaoyingwang@fudan.edu.cn.|Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China. xiaoyingwang@fudan.edu.cn.
authors.forename: Xiao-Ying
authors.initials: XY
authors.lastname: Wang
authors.affiliation: Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, People's Republic of China. gao.qiang@zs-hospital.sh.cn.|Biomedical Research Center, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China. gao.qiang@zs-hospital.sh.cn.|Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China. gao.qiang@zs-hospital.sh.cn.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Gao
mesh_terms: D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D006528:Carcinoma, Hepatocellular / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D054415:Chemokine CCL19 / Q000378:metabolism; D054421:Chemokine CCL21 / Q000378:metabolism; D015331:Cohort Studies; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D008113:Liver Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D054388:Receptors, CCR / Q000378:metabolism*; D054400:Receptors, CCR7 / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: C408223:ACKR4 protein, human; D014408:Biomarkers, Tumor; C515460:CCL19 protein, human; C515478:CCL21 protein, human; C515370:CCR7 protein, human; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D054388:Receptors, CCR; D054400:Receptors, CCR7; D053773:Transforming Growth Factor beta1
keywords: CCR7; CCRL1; Treg-like; Tumor microenvironment
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