Abstract: Colon cancer (CoCa) remains the third leading cause of cancer-related deaths because chemotherapeutics currently offered to treat early and advanced CoCa fail to achieve optimal clinical response, and patients often develop resistance and suffer severe toxicity. Therefore, a more efficacious treatment option with lower toxicity is crucial to improve CoCa clinical outcomes. To achieve this objective, we propose investigating the role of CC chemokine receptor 6 (CCR6) and its ligand CCL20 on cellular and molecular mechanisms contributing to the poor outcome of currently offered chemotherapeutics (5FU and Oxaliplatin) and develop more effective and less toxic treatment. The proposed investigation is based on our published and preliminary data showing (i) higher CCR6 expression in CoCa cells and tissues; (ii) CCR6 expression positively correlates with disease stage; (iii) CCR6/CCL20 is biologically active and promotes migration and invasion of CoCa, (iv) CCR6/CCL20 activates β-catenin, Snail, vimentin, α-SMA and down regulates E-cadherin indicating the significance of this axis in maintaining mesenchymal phenotype known to be less responsive to chemotherapy. Based on this, we hypothesize that the CCR6-CCL20 axis supports cellular and molecular reprogramming to escape chemotherapeutics and developing therapeutics directed to CCR6/CCL20 will improve chemotherapeutic efficacy. The hypothesis will be tested using the following aims. Aim 1: Define the CCR6- mediated molecular mechanism(s) associated with the poor chemotherapeutic response. Under this aim, using genomics and proteomics approach, we will determine the impact of the CCR6/CCL20 axis on the molecular detour cancer cells take to promote cellular and molecular phenotypes that help omit cytotoxic effects of conventional chemotherapeutics. Additionally, we will ascertain if blocking CCR6/CCL20 axis will improve cytotoxicity of 5-FU and Oxaliplatin at a suboptimal dose. Further, using clinical samples, we will establish the impact of CCR6/CCL20 on chemotherapeutic response. Aim 2: Determine the effect of CCR6 inhibition on the chemotherapeutic response in vivo. Using xenograft and syngenic murine model, this aim will determine the impact of CCR6/CCL20 axis inhibition on the efficacy of 5-FU and Oxaliplatin in vivo. The syngenic model will allow us to ascertain the effects of CCR6/CCL20 inhibition on systemic and tumor immunity with or without 5-FU and Oxaliplatin. Endpoint analysis of tumor and serum will determine the alteration in cellular and molecular mechanisms involved in improving the chemotherapeutic efficacy and organ toxicity. Completing this aim will provide the rationale for using CCR6/CCL20 directed therapy as a new treatment modality. This proposed research is novel since the impact of CCR6/CCL20 on cellular and molecular reprogramming contributing to poor 5-FU and Oxaliplatin response is untested both in vitro and in vivo. Information obtained from this study will be signif...