Abstract
The aim of this study was to investigate the prognostic value of chemokine receptor CCR7 expression and intratumoral FOXP3+ regulatory T cells (Tregs) in gastric cancer. CCR7+ tumor cells and FOXP3+ Tregs were assessed by immunohistochemistry in tissue microarrays containing gastric cancer from 133 patients. Prognostic effects of low or high CCR7 and FOXP3 expression were evaluated by Cox regression and Kaplan-Meier analysis, as well as the correlation between CCR7 positive score and intratumoral FOXP3+ cell number in a longitudinal assessment. The analysis showed that the high expression levels of CCR7 and FOXP3 were detected in 69.9% and 65.4% of cases, respectively. High CCR7 expression in gastric cancer cells was significantly associated with poor overall survival (OS) (P = 0.010) and lymph node metastasis (P = 0.009), and was an independent factor for worse OS (P = 0.023) by multivariate analysis. High numbers of intratumoral FOXP3+ Tregs significantly correlated with shorter OS (P = 0.021) and lymph node metastasis (P = 0.024), and was also an independent factor for adverse OS (P = 0.035). Furthermore, there was a significantly positive correlation between CCR7 positive score and intratumoral FOXP3+ cell number (r = 0.949, P<0.001). These results revealed that CCR7 expression in gastric cancer cells and intratumoral FOXP3+ Tregs could be considered as a co-indicator of clinical prognosis of gastric cancer.
Highlights
CCR7 is a seven transmembrane G protein-coupled chemokine receptor, mainly expressed on the cell surface of naive T cells and dendritic cells (DCs), SLC and ELC (EB11-ligand chemokine, CCL19) are its two high-affinity ligands
The tumor size of 79 (59.4%) patients was less than 40 mm and that of others was more than or equal to 40 mm. 75 (56.4%) patients had lymphatic invasion and 84 (63.2%) patients had lymph node metastasis. 61 (45.9%) tumors were undifferentiated and others were differentiated. 50 (37.6%) tumors were categorized as T1T2, and 83 (62.4%) as T3T4 according to Japanese Gastric Cancer Association (JGCA)
Cells were considered as FOXP3+ Tregs based on distinct intranuclear expression (Fig. 2 A–D)
Summary
CCR7 is a seven transmembrane G protein-coupled chemokine receptor, mainly expressed on the cell surface of naive T cells and dendritic cells (DCs), SLC (secondary lymphoid chemokine, CCL21) and ELC (EB11-ligand chemokine, CCL19) are its two high-affinity ligands. CCR7 is essential for the migration of T cells and DCs to the surrounding lymphoid tissue or the site of immune response by binding to its ligands [1]. CCR7 is expressed in naive T cells and DCs, and in some tumor cells. Tumors with high CCR7 expression are more likely to exhibit extrathyroidal extension, angiolymphatic invasion, lymph node metastasis, antiapotosis and cell proliferation [2,3,4]. Many studies have shown that malignant cells with CCR7 expression can be directed to the corresponding organs with high presence of their ligands [5,6,7,8]. CCR7 expression in tumor cells is closely correlated with their metastasis and malignancy [2]
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