Project Summary/Abstract Pancreatic ductal adenocarcinoma (PDAC) has the highest mortality rate of all major cancers. While immunotherapy has revolutionized treatment for numerous cancers, such treatments for patients with pancreatic ductal adenocarcinoma (PDAC) have not been successful. Failure of the current immunotherapeutic approaches are due to numerous features of pancreatic tumors including; poor immunogenicity and a highly immunosuppressive tumor microenvironment (TME). Macrophages are considered as a focal point for interventional studies during PDAC given that they regulate immunosuppression, promote a pro-fibrotic microenvironment, as well as play an essential role in promoting tumor progression along local nerves. The autonomic nervous system work in close partnership with local macrophages. Autonomic nerves stimulate cytokine and chemokine production in macrophages that contribute to their aforementioned functions, however, the signaling mechanisms by which nerves communicate with the immune system and coordinate the release of tumorigenic factors are unknown. Based on our preliminary data, I hypothesize that noradrenaline (NA) released from sympathetic nerves binds to adrenergic receptors on sympathetic nerve associated macrophages (SAMs), which consequently support tumor progression. To study the communication between local pancreatic nerves and immune cells, we are using ex vivo pancreatic tissue slices from human and mouse PDAC tumors. With this technological platform, we are able to visualize nerves, macrophages, and tumor cells with minimal disruption from their natural state. We will characterize [Ca2+]i responses in macrophages in response to autonomic neurotransmitters, as well as use a targeted in-vivo approach in order to determine if blocking adrenergic signaling within immune cells promotes anti-tumor responses. Combined with our preliminary physiological data, we will use molecular approaches to further explore this crosstalk. We expect our results to identify communication networks between macrophages, tumor cells and autonomic nerves in the setting of PDAC perineural invasion that will prompt new therapeutic approaches for this deadly disease.