Targeting interleukin-17 receptors

During the last decade, increasing evidence suggests a strong association between chronic inflammation and cancer development among different types of cancer. The dysregulation of pro-inflammatory cytokines or their receptors is a common feature observed in many cancers [1]. Cancer cells take advantage of cytokine or cytokine receptor overexpression to benefit their own growth or invasive capacity via the autocrine or paracrine loop. The improved understanding about the crosstalk between cancer cell and tumor microenvironment may raise the foundations for development of novel drugs in cancer treatment. Pancreatic cancer is a malignant diseases associated with significant intraand peri-tumoral inflammation. Recently, we showed that the pro-inflammatory autocrine/ paracrine IL-17B/IL-17RB signaling is essential for pancreatic cancer malignancy [2]. Overexpression of IL17RB strongly correlates with post-operative metastasis and inversely correlates with progression-free survival in pancreatic cancer patients. The activated IL-17B/IL-17RB signaling pathway increases the tumorigenic and metastatic abilities of pancreatic cancer cells. The expressions of CCL20, CXCL1, IL-8, and TFF1, induced by autocrine/ paracrine IL-17B/IL-17RB signaling through ERK1/2 pathway in pancreatic cancer cells, enhance inflammation in the tumor microenvironment via recruiting neutrophils, MQ and lymphocytes, which further support cancer cells survival and facilitate metastasis. Likewise, chemokines induced by IL-17B/IL-17RB may also be secreted from stromal cells and participate in MQ and endothelial cell recruitment to promote pancreatic cancer progression. Except for TFF1 that is predominantly expressed in cancer cells, CCL20, CXCL1 and IL-8 can be detected both in pancreatic cancer cells and tumor surrounding stroma, particularly in inflammatory cells, suggesting a vicious cycle between cancer cells and infiltrating immune cells in promoting tumor malignancy as illustrated in Figure 1. It appears that IL-17B/IL-17RB signaling enhances cancer cell malignancy and simultaneously remodels its microenvironment (i.e. MQ and vasculogenic endothelial cells recruitment) to facilitate metastasis by, in part, secreting these chemokines. Taken together, the IL-17B/ IL-17RB signaling not only emerges as an important regulator of pancreatic cancer growth and metastasis, but also serves as an obvious target for pancreatic cancer treatment [2]. To translate this finding into a potential clinical application, a monoclonal antibody recognizing the native form of IL-17RB was generated. Treatment with this newly made monoclonal antibody not only effectively blocks pancreatic tumor metastasis, but also significantly prolongs survivals in a mouse xenograft model. These results suggest that IL-17B/IL17RB signaling is a major contributor to the highly aggressive characteristics of pancreatic cancer, and provide a practical approach to tackle this disease [2]. Similarly, blocking IL-17RB signal reduces breast tumor growth [3]. Thus, targeting IL-17B/ IL-17RB is likely a useful approach for treating cancers with this activated pathway. The presence of other IL-17 members in tumor microenvironment has been reported as a part of the inflammatory conditions that promotes tumorigenesis and metastasis. The IL-17 family consists of six cytokines, IL17A through IL-17F, with 20-50% sequence homology. IL-17A and IL-17F are pro-inflammatory cytokines Editorial