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

Abstract

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 Apc^Min/+ mouse model. Ablation of CCR2 in Apc^Min/+ mice significantly increased the overall survival and reduced intestinal tumor burden. Immune cell analysis showed that CCR2^-/- Apc^Min/+ 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 Apc^Min/+ mice. The CCR2^-/- Apc^Min/+ tumors showed significantly reduced levels of interleukin (IL)-17 and IL-23 and increased IFN-γ and Granzyme B compared to Apc^Min/+ tumors. Transfer of CCR2^+/+ Apc^Min/+ 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^-/- Apc^Min/+ 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.

Keywords: ApcMin/+ mice; CCR2; IL-17; intestinal tumorigenesis.