Absence of <scp>CCR2</scp> reduces spontaneous intestinal tumorigenesis in the <scp>Apc<sup>Min</sup></scp><sup>/+</sup> mouse model
Venkatakrishna R. Jala, Sobha R. Bodduluri, Sweta Ghosh, Zinal Chheda, Rajbir Singh, M. Estellie Smith, Paula M. Chilton, Christopher Fleming, Steven Mathis, Rajesh Sharma, Rob Knight, Jun Yan, Bodduluri Haribabu
Abstract
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.