Peripheral Nerve Regulation of Pancreas Cancer Progression

Abstract Pancreatic cancer is the third leading cause of cancer deaths in the United States and most patients are refractory to currently available therapies. However, we have observed that sensory denervation slows or even halts the progression from precancer stages to malignant disease in a transgenic mouse model of pancreatic ductal adenocarcinoma. This work contributed to a resurgence of interest in understanding the role of the nervous system in cancer with the thought being that targeting nerves could be a novel way to improve therapeutic efficacy. We have found that both sensory and sympathetic neurons express membrane bound proteins recognized by immunologists as checkpoint proteins. Specific Aim 1 of this study will examine the impact of sensory nerves on immune cell functions within the emerging tumor microenvironment, including the specific contribution of neuronally expressed immune checkpoint proteins to tumor growth and immune responses. Importantly, both sensory and sympathetic nerves have also been implicated in the development of secondary lymphoid structures. In Specific Aim 2 of this study, we will evaluate changes in the innervation of draining lymph nodes. We will examine whether changes in sensory and sympathetic innervation of the lymph nodes or neural expression of checkpoint proteins contribute to a pro-tumorigenic immune response. We will also determine if the lymph node innervating nerves are a therapeutic target and/or a prognostic biomarker. Finally, in Specific Aim 3, we will evaluate whether combining chemotherapy or checkpoint therapy with interventions that directly target peripheral nerves improves therapeutic efficacy. Overall these studies will provide essential information about novel neuro-immune pathways that can be used to improve patient care.