Division of Surgical Oncology
Dept of Microbiology, Immunology and Cell Biology
West Virginia University
Targeting Peptidyl Arginine Deiminase 4 (PAD4) Induced Neutrophil Extracellular Trap (NET) Formation to Enhance T cell Response in Pancreatic Adenocarcinoma
Aim: Basic Science / Cancer Biology
Pancreatic cancer is an aggressive disease characterized by inability of the immune system to fight the tumor. We have identified a process in pancreatic cancer, neutrophil extracellular trap formation (NETs) that may play a critical role in this weakened immune response. NETs occur when specific immune cells, neutrophils, become activated and expel all their contents outside the cell. This forms a web of DNA and other materials that contributes to the growth of tumor cells. We have recently discovered that mice incapable of forming NETs due to genetic deletion of PAD4, a critical part of the NET machinery, have decreased pancreatic tumor growth. Fortunately, there are specific drugs that target NETs and PAD4, known as PAD4 inhibitors. Our goal is to test these drugs in animal models of pancreatic cancer to determine if they can prevent tumor growth and the spread of the cancer to other organs. These valuable studies are the first step towards the potential for PAD4 inhibitors to be used as novel treatment in patients with pancreatic cancer at a time when new approaches are desperately needed. In addition to determining the efficacy of PAD4 inhibitors, we will also study how the drugs impact the body’s immune response to the tumor. We believe that by inhibiting PAD4/NETs, we will activate the immune system to fight the cancer. These studies will improve our understanding about how PAD4/NETs function and potentially lead to novel combination therapies with other new drugs that also augment the immune response.