CCR2 promotes intestinal tumorigenesis through enhancing inflammation via IL-17 and IL-23 pathway

Abstract

Abstract Chemokines and their receptors have been implicated in several cancers and metastasis including colon cancer. CCL2, a classic chemokine mediates biological functions via CCR2 receptor. In this study, we investigated the role of CCR2 in progression of intestinal tumors using spontaneous intestinal tumorigenesis mouse model, ApcMin/+ mice. Ablation of CCR2 in ApcMin/+ mice significantly increased the survival, reduced tumor burden and corrected immune abnormalities caused by ApcMin/+ mutation. Immune cell analysis in spleen and mesenteric lymph nodes (mLNs) suggested that CCR2−/−ApcMin/+ mice exhibited significant reduction in myeloid cell population and increase in IFNγ producing T-cell populations compared to ApcMin/+ mice. CCR2−/−ApcMin/+ mice also displayed decreased tumor infiltrating F4/80+ and increased CD8+ cells. Polyps in CCR2−/−ApcMin/+ displayed significant reduction in IL-17 and IL-23 cytokines compared to polyps of ApcMin/+. Adoptive transfer of splenic CD4+ T cells from ApcMin/+ mice into Rag2−/− mice develops severe colitis. However, transfer of CD4+ T cells from CCR2−/− ApcMin/+ failed to develop colitis in Rag2−/− mice. The levels of IL-17 in these mice significantly reduced suggesting importance of CCR2 expression on CD4+cells to promote IL 17 mediated colonic inflammation. Microbiota analysis revealed that ablation of CCR2 in ApcMin/+ lead to decrease in tumor promoting Bacteroides genus compared to ApcMin/+. In conclusion, CCR2 plays a critical role in enhancing tumor-promoting inflammation via IL-17 and IL-23 leading to increased intestinal tumorigenesis in ApcMin/+ mice. Blocking CCR2-CCL2 axis potentially offers an alternative therapeutic option to control intestinal tumorigenesis.