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
Atypical chemokine receptor
ChemoCentryX chemokine receptor
Time to recurrence
Integrated optical density
Barcelona clinic liver cancer
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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.
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