Abstract
BackgroundTumor-associated macrophages (TAMs) remodel the colorectal cancer (CRC) microenvironment. Yet, findings on the role of TAMs in CRC seem to be contradictory compared with other cancers. FoxP3+ regulatory T (Treg)-cells dominantly infiltrate CRC. However, the underlying molecular mechanism in which TAMs may contribute to the trafficking of Treg-cells to the tumor mass remains unknown.Methodology/Principal FindingsCRC was either induced by N-methyl-N-nitrosourea (MNU) and H. pylori or established by subcutaneous injection of mouse colorectal tumor cell line (CMT93) in mice. CMT93 cells were co-cultured with primary macrophages in a transwell apparatus. Recruitment of FoxP3 green fluorescence protein positive (FoxP3GFP+) Treg-cells was assessed using the IVIS Imaging System or immunofluorescence staining. A role for macrophages in trafficking of Treg-cells and in the development of CRC was investigated in CD11b diphtheria toxin receptor (CD11b-DTR) transgenic C57BL/6J mice in which macrophages can be selectively depleted. Treg-cells remarkably infiltrated solid tumor, and predominantly expressed the homing chemokine receptor (CCR) 6 in the induced CRC model. Both CMT93 cancer cells and macrophages produced a large amount of CCL20, the sole ligand of CCR6 in vitro and in vivo. Injection of recombinant mouse CCL20 into tumor sites promoted its development with a marked recruitment of Treg-cells in the graft CRC model. Conditional macrophage ablation decreased CCL20 levels, blocked Treg-cell recruitment and inhibited tumor growth in CD11b-DTR mice grafted with CMT93.Conclusions/SignificanceTAMs recruit CCR6+ Treg-cells to tumor mass and promote its development via enhancing the production of CCL20 in a CRC mouse model.
Highlights
Colorectal cancer (CRC) is one of the most common cancers worldwide, and the fourth most common cause of cancerassociated death [1]
Numbers of FoxP3+ Treg-cells were increased in tumorinfiltrating lymphocytes of colorectal cancer (CRC) in mice A major goal of the present study was to provide a definitive demonstration of the trafficking mechanism for FoxP3+ Treg-cells in CRC in vivo
After 80 weeks, 85% mice used in this study developed visible CRC induced by MNU and H. pylori (Figure 1A–C)
Summary
Colorectal cancer (CRC) is one of the most common cancers worldwide, and the fourth most common cause of cancerassociated death [1]. Similar to other types of cancer, CRC arises in chronically inflamed tissue, and its development is under immune surveillance and depends on cytokines and chemokines secreted from tumor-infiltrating immune cells [2]. Increased numbers of Treg-cells have been reported in the blood and tumors of patients with various cancers, including breast cancer, colorectal cancer, esophageal cancer, gastric cancer, hepatocellular carcinoma, leukemia, lung cancer, lymphoma, melanoma, ovarian cancer, and pancreatic cancer [4]. In patients with CRC, an increased numbers of Treg-cells in peripheral blood, mesenteric lymph nodes and directly within the tumor were observed [5,6]. Tumor-associated macrophages (TAMs) remodel the colorectal cancer (CRC) microenvironment. FoxP3+ regulatory T (Treg)-cells dominantly infiltrate CRC. The underlying molecular mechanism in which TAMs may contribute to the trafficking of Treg-cells to the tumor mass remains unknown
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