Absence of CCR2 reduces spontaneous intestinal tumorigenesis in the ApcMin/+ mouse model

The biological activities of chemokine (C‐C motif) ligand 2 (CCL2) are mediated via C‐C chemokine receptor‐2 (CCR2). Increased CCL2 level is associated with metastasis of many cancers. In our study, we investigated the role of the CCL2/CCR2 axis in the development of spontaneous intestinal tumorigenesis using the ApcMin/+ mouse model. Ablation of CCR2 in ApcMin/+ mice significantly increased the overall survival and reduced intestinal tumor burden. Immune cell analysis showed that CCR2−/−ApcMin/+ mice exhibited significant reduction in the myeloid cell population and increased interferon γ (IFN‐γ) producing T cells both in spleen and mesenteric lymph nodes compared to ApcMin/+ mice. The CCR2−/−ApcMin/+ tumors showed significantly reduced levels of interleukin (IL)‐17 and IL‐23 and increased IFN‐γ and Granzyme B compared to ApcMin/+ tumors. Transfer of CCR2+/+ApcMin/+ CD4+ T cells into Rag2−/− mice led to development of colitis phenotype with increased CD4+ T cells hyper proliferation and IL‐17 production. In contrast, adoptive transfer of CCR2−/−ApcMin/+ CD4+ T cells into Rag2−/− mice failed to enhance colonic inflammation or IL‐17 production. These results a suggest novel additional role for CCR2, where it regulates migration of IL‐17 producing cells mediating tumor‐promoting inflammation in addition to its role in migration of tumor associated macrophages. What's new? Chronic inflammation is a well‐known promoter of colon cancer. Although CCR2 is a critical chemokine receptor for the recruitment of macrophages to inflammatory sites, its role in the migration of tumor‐infiltrating immune cells remains unclear. Here, in the ApcMin/+ mouse model for spontaneous intestinal tumorigenesis, CCR2 ablation increased overall survival, reduced intestinal tumor burden, and decreased IL‐17‐producing CD4+ T cells. Furthermore, lack of CCR2 in ApcMin/+ CD4+ T cells reduced IL‐17 expression and led to insufficient numbers to promote colonic inflammation. Altogether, the results suggest a novel role for CCR2 in regulating IL‐17‐producing CD4+ T cells to promote intestinal tumorigenesis.