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.

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