THE ROLE OF THE IL-17/IL-17R AXIS IN BREAST TUMOR GROWTH AND METASTASIS

Abstract

Clinical trials and animal experiments have revealed that chronic inflammation may contribute to all steps of tumor development from initiation, all the way to metastatic progression, predisposing for the development of many types of cancer including breast cancer. Interleukin-17A (IL-17A), the hallmark cytokine of T helper-17 (Th17) cell subset, has an important role in mediating chronic inflammation as a pro-inflammatory cytokine. IL-17A-producing cells are detected in various cancer samples; however, existing information on the role of the IL-17/IL-17R axis in cancer remains paradoxical. In this study, an adenoviral delivery system was used to over-express IL-17A (AdIL-17A) or IL-17RA antagonist (AdIL-17RA:Fc) in 4T1 murine mammary carcinoma cells. These cells were used to investigate the specific role of IL-17A in breast cancer using a murine model. Our study demonstrates that IL-17A, promotes breast tumor growth via reinforcement of myeloid-derived suppressor cells (MDSCs) that dampen the immunosurveillance response, and increased lung metastasis via chemokine-mediated attraction of tumor cells into lungs. However, the pro-tumor effect of IL-17A could be reversed into an anti-tumor one when the tumor was resected. This reversal could be due to surgery-mediated reduction of MDSCs following tumor resection and IL-17A-mediated activation of CD4 (Th1) and CD8 (CTLs) cells, which would favor an anti-tumor response. This study provides novel insights into the role of IL-17/IL-17R axis in breast tumor development and has major implications for targeting IL-17A in the treatment of tumors.