Role of environmental toxins in shaping the tumor immune microenvironment

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ABSTRACT Pancreas adenocarcinoma (PDAC) is the third leading cause of cancer related deaths in the United States and remains among the most lethal cancers with an expected 5-year survival of <10%. Environmental exposures to chemicals such as those found in cigarette smoke, Agent Orange (dioxin; TCDD) and diet may underlie a continued rise in PDAC incidence in veterans through unknown mechanisms. Strong evidence implicates chronic inflammation as the link between exposure to toxins and PDAC tumorigenesis though the exact mediators remain unknown. Interleukin-22 (IL22) has emerged as an important cytokine in host defense and tissue repair in the pancreas. Although generally protective, chronically elevated levels have been implicated in development of dysplasia and cancer. A defining feature of IL22-producing cells is their reliance on the toxin binding, aryl hydrocarbon receptor (AhR), thought to represent an “environmental sensor” of the immune system, and recently implicated in increased pancreatic IL22 signaling. We recently discovered that AhR ligands promote IL22 production which can induce early malignant transformation of pancreatic epithelial cells through enhancement of ERK signaling positioning IL22 as the possible missing link in toxin mediated carcinogenesis. Important questions remain unanswered including the critical immune components in IL22 secretion in physiologic and pathologic states. Also unknown is the target of cytokine signaling with previous reports of activity in both fibroblasts and epithelial cells. Little is known about reliance of tumors on sustained IL22 signaling for persistence and growth, a factor that has important therapeutic implications. In this research proposal, we will use reporter mice to identify the cellular sources of IL22 in both the normal and cancerous pancreas and define the role of AhR ligands in activating these cells. We will also investigate the principle target of IL22 signaling in the pancreas as this could provide greater insights into the AhR/IL22 axis during tumor development. Finally, we will determine if AhR blockade could serve as a clinically useful method of disrupting toxin mediated tumorigenesis. Successful completion of this proposal will uncover an important link between environmental exposures, inflammation and cancer formation and identify a novel mechanism by which tissues interface with toxins in the microenvironment. Development of a strategy to decrease a factor previously identified as a causative agent in chronic pancreatitis and cancer formation will have direct translatability to veterans with PDAC as well as other exposure-related malignancies.