Abstract 1417: CXCR2 plays critical roles in colitis and colitis-associated cancer through trafficking of myeloid-derived suppressor cells.

Abstract

Abstract A large body of evidence indicates that chronic inflammation is a risk factor for colorectal cancer (CRC). However, all of the mechanisms by which inflammation promotes CRC development are not fully understood. Our lab previously showed that PGE2 promotes CRC progression through angiogenic chemokine CXCL1 (Wang et al., 2006). CXCL1 exerts its downstream functions via binding to its receptor, CXCR2, which is a G-protein-coupled receptor. Our previous study showed that CXCR2 expression is also elevated mainly in endothelial and immune cells of human colorectal carcinomas. CXCR2 is expressed on neutrophils and involved in neutrophil trafficking. These results prompted us to hypothesize that CXCR2 may be one of mediators connecting inflammation and CRC. To address this question, preliminary experiments were performed to determine whether CXCR2 is involved in inflammation-enhanced CRC progression. Our results revealed that deletion of CXCR2 significantly attenuated AOM/DSS induction of chronic colonic inflammation and tumor burden, suggesting that CXCR2 is required for promoting chronic inflammation and tumor formation and growth in the colon. Among immunocytes we tested, loss of CXCR2 only significantly suppressed a massive infiltration of MDSCs (CD11b+Ly6G+) into the colonic mucosa in both normal (water treatment) and chronic inflammatory (DSS treatment) conditions. We further found that the status of CXCR2 did not affect MDSC populations in the bone marrow of mice treated with either water or DSS. Interestingly, treatment with DSS more dramatically reduced MDSC populations in the circulatory system of WT mice than of CXCR2 knockout mice, suggesting that CXCR2-deficient MDSCs have less ability to migrate to local organs. Our in vitro results further demonstrated that treatment with CXCL1 or CXCL5 were able to induce chemotaxis of WT-mice derived MDSCs but not MDSCs isolated from CXCR2-/- mice. Collectively, these results suggest that CXCR2-expressing MDSCs contribute to chronic inflammation and colitis-associated tumor formation and growth. Our findings are novel and provide a rationale for development of new therapeutic approaches to subvert tumor-induced immunosuppression by using CXCR2 antagonists and neutralized antibodies. Citation Format: Hiroshi Katoh, Dingzhi Wang, Sun-Hee Kim, Raymond N. DuBois. CXCR2 plays critical roles in colitis and colitis-associated cancer through trafficking of myeloid-derived suppressor cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1417. doi:10.1158/1538-7445.AM2013-1417