Washington University in St. Louis (WU)
Patients with pancreatic ductal adenocarcinoma (PDAC) face a bleak prognosis mainly because of limited treatment options. Hence, novel and effective treatment is urgently needed. In p48-Cre/LSL-KRASG12D mice, chemical-induced pancreatitis markedly accelerates PDAC progression through engagement of Toll-like receptors (TLRs) 7 and 9 (1-3). In addition, autocrine IL1-IKK-NF-?B signaling is necessary for PDAC development in a mouse model (4,5). The TLRs and IL-1 receptors are the core receptors in innate immunity (6), ubiquitously present in all cell types (7), and engages MyD88 and the Interleukin-1-associated kinases (IRAKs) especially IRAK4 to activate Transforming growth factor ß activated kinase 1 (TAK1/MAP3K7) which controls the IKK-NF-?B, p38/MAPK, and type-1 interferon pathways (8,9). Serial work in the Lim Lab showed that the IRAK4 innate immune pathway critically mediates local and systemic inflammation in PDAC has significant impact on adaptive T cell response. (10-13).