Targeting CCL20-CCR6 Interactions in Colorectal Cancer

Va Boston Health Care System, Boston MA

Investigators

Linked publications & trials

Abstract

Background and Innovation: Novel treatment strategies for colorectal cancer are desperately needed. Despite significant advances in the treatment of metastatic disease, patients healthy enough to receive intensive therapy still only survive 2-3 years. Chemokines have emerged as a crucial link between tumor- promoting inflammation and cancer. CCR6 is the only known receptor for the inflammatory chemokine CCL20, which in turn is the only known chemokine ligand for CCR6. Several lines of evidence suggest that interactions between the inflammatory chemokine CCL20 and its receptor CCR6 play a key role in the development and progression of colorectal cancer. To date, however, beyond our preliminary results, there is a paucity of in vivo data on the effect of disrupting CCL20-CCR6 interactions in colorectal cancer in the setting of an intact immune system or in testing how targeting CCL20-CCR6 interactions can be rationally integrated into the treatment of colorectal cancer. We have found that CCL20-CCR6 interactions promote intestinal carcinogenesis and colorectal cancer growth in animal models. We have observed that CCL20-CCR6 interactions induce tumor-promoting effects, such as proliferation, migration, EMT and further secretion of CCL20, on neoplastic epithelial cells. Blockade of CCL20 abrogates colorectal cancer neoplastic epithelial cell migration, proliferation and EMT mediated by inflammatory tumor conditions. We have shown that autocrine HGF-c-MET and MSP-MSPR signaling pathways mediate tumor-promoting effects on neoplastic epithelial cells induced by CCL20-CCR6 interactions. In addition to the effects on neoplastic epithelial cells, we have found that CCL20-CCR6 interactions in tumor stroma promote colorectal cancer as transplanted colon cancer cells expressing CCR6 had delayed growth in CCR6-deficient host mice. We identified macrophages as an important mediator of this stromal tumor-promoting effect. Macrophage infiltration is decreased in the setting of CCR6 deficiency in mice, and CCL20 induces monocyte/macrophage migration in vitro and in vivo. Transplanted colon cancer growth is delayed by depletion of tumor macrophages. Furthermore, we have found that tumor macrophages secrete inflammatory mediators that induce proliferation of colon cancer cells. Recently, we have begun to investigate targeting CCL20-CCR6 interactions in combination with the use of approved therapeutic agents for colorectal cancer. Notably, we have found that 5-FU induces secretion of CCL20, and that blockade of CCL20-CCR20 interactions improves the efficacy of 5-FU and cetuximab cell killing. Thus, we hypothesize that targeting the CCL20-CCR6 axis can improve the treatment of colorectal cancer. To test this hypothesis, and to further elucidate the role of the CCL20-CCR6 axis in colorectal cancer, we aim to: 1) identify novel targets for colorectal cancer in the CCL20-CCR6 axis; 2) characterize the changes in the immune microenvironment of colorectal cancer induced by targeting CCL20-CCR6 interactions; and 3) evaluate the role of targeting CCL20-CCR6 interactions in sensitizing colorectal cancer to treatment with approved systemic agents. This project has several innovative aspects including: targeting a pathway with the potential to affect both neoplastic cells and tumor stroma; exploration of a target with promise of enhancing existing treatments; the use of cutting-edge models and methods; and evaluation of a novel therapeutic. Significance and Impact to Veterans Healthcare: This project has the potential to improve the treatment and outcome for colorectal cancer patients. Colorectal cancer screening and optimal treatment delivery are major targets for quality improvement in VHA. Colorectal cancer affects 4,000 patients each year in VHA. Path to translation/implementation: The proposed studies will shed light on the role of the CCL20-CCR6 axis in colorectal cancer. We believe that these studies will determine the clinical relevance and therapeutic importance of interactions between CCR6 and CCL20 in this disease and should pave the way to integrate targeting of this pathway in the treatment of colorectal cancer for human patients.