Dissecting the role of Notch signaling in the pancreatic cancer microenvironment.

Project Summary/Abstract Pancreatic cancer is marked by an immunosuppressive tumor microenvironment contributing to the overall therapeutic resistance seen in this deadly malignancy. Although Notch signaling is integral in the progression of pancreatic neoplasia, its role in the establishment and maintenance of the immunosuppressive tumor microenvironment is unclear. The long-term goal is to define the role of intercellular signaling pathways like Notch in the treatment resistance in pancreatic cancer. The overall objective of this application is to define how Notch regulates myeloid and, as a consequence, T cell polarization in the pancreatic tumor microenvironment to regulate its immunosuppressive nature. The central hypothesis of the application is that Notch serves as one of the key regulatory pathways promoting the establishment of immunosuppressive myeloid and exhausted or anergic T cell populations. The rationale for this proposal is that understanding the mechanistic basis and effects of Notch signaling on the pancreatic tumor microenvironment will identify new approaches to sensitize pancreatic cancer to existing therapies including immunotherapy. The central hypothesis will be tested through three specific aims – 1. Dissect Notch signaling in the pancreatic cancer microenvironment; 2. Define the mechanism and direct effects of Notch signaling on myeloid polarization and function; 2. Target Notch signaling to alleviate immune suppression in pancreatic cancer. We will use a combination of human and mouse pancreatic cancer samples, genetically engineered mouse models, orthotopic tumor models, and human and murine tumor cell lines will be used. In addition, we will use human organoids and cancer associated fibroblasts, together with patient-matched immune cells. Notch signaling will be disrupted via genetic and pharmacologic approaches both in vivo and in vitro to define its role in myeloid compartment function. The proposed work is innovative because it defines novel roles of Notch signaling in pancreatic cancer outside its known epithelial function. It is significant because it allows for the potential development of new immunomodulatory treatments for this deadly disease.