Pancreatic cancer is an aggressively metastatic cancer with a high mortality rate, but the mechanisms underlying this aggression are not yet fully understood. In this issue, Wu et al. shed some light on this subject. They report that pancreatic cancer cells depend on IL-17B receptor (IL-17RB) signaling for maintenance of their malignant and metastatic properties. With pancreatic cancer slated to become the second leading cause of cancer death in the US by 2020, these findings are timely and important.
Perhaps even more than most cancers, pancreatic ductal adenocarcinoma is characterized by extremely robust interactions between malignant epithelial cells and the surrounding tumor microenvironment. Within this microenvironment, abundant extracellular matrix, activated fibroblasts, proinflammatory macrophages, and immunosuppressive myeloid and lymphoid elements all conspire to create a dense barrier to chemotherapeutic and immune assault.
Using both gain- and loss-of-function studies, Wu et al. show that IL-17B and IL-17RB potently support the anchorage-independent growth, invasion, tumorigenicity, and metastasis of human pancreatic cancer cells, mediated in part by downstream cytokine activation and macrophage recruitment. In addition to supporting the intrinsic malignancy of pancreatic cancer cells, the current report also implicates IL-17 signaling in the creation of a proinflammatory microenvironment. The authors also demonstrate that treatment with a monoclonal antibody targeting IL-17RB extends survival in an orthotopic xenograft model. These results may have direct clinical relevance, as additional data suggest that high-level expression of IL-17RB is associated with shortened progression-free survival in patients with pancreatic cancer.
This study complements another recent report from McAllister et al. implicating hematopoietic-to-epithelial IL-17 signaling as a requisite driver of preinvasive pancreatic cancer. Together, these two studies suggest that IL-17 signaling is required during all stages of pancreatic cancer, from preinvasive inception to metastatic spread. Given the fact that clinical trials of IL-17 inhibition are already under way in a variety of proinflammatory conditions, including psoriasis and rheumatoid arthritis, these studies clearly set the stage for similar trials in patients with pancreatic cancer.
There are a number of unresolved issues and caveats with these studies. It is possible that protumorigenic IL-17 activity is confined to specific subsets of patients with pancreatic cancer, as the current study suggests that ∼40% of pancreatic cancers display detectable IL-17RB expression as assessed by immunohistochemistry. In addition, some studies have suggested that IL-17 might exert antitumor effects in the context of vaccine-augmented immune responses; it is therefore possible that IL-17 signaling may exert opposing influences on pancreatic tumorigenesis in the context of variability in the host immune response.
These caveats aside, this study contributes to the growing realization that interrupting IL-17 and other interleukins may soon become an important therapeutic option for an otherwise deadly disease.
