Mechanistic investigations of microbiome-driven aryl hydrocarbon receptor activity and macrophage function in pancreatic cancer.

Abstract public domain (NIH RePORTER)

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer- related death. This is attributable to the asymptomatic early stages of disease, the fibrotic nature of the tumor, and the lack of response to surgery, chemo- and immunotherapies. The lack of response to immunotherapy is despite the fact that pancreatic cancer exhibits a significant immune infiltrate. Relatively little is understood about the immune landscape in PDAC, but it is clear that suppressive populations of macrophages likely play a key role in shaping the tumor microenvironment and targeting them could impact responses to therapy. Likewise, altered microbiome activity has been linked to pancreatic cancer progression, resistance to immune therapy, and survival times in patients. Recently we described a critical role for the aryl hydrocarbon receptor (AhR) as a driver of macrophage suppressive function. Since AhR is an important sensor of microbial metabolites, we surmised that the microbiome may drive tumor macrophage function via the metabolic products produced by the flora; while blocking AhR activity would cause the tumor microenvironment to become “hot” enhancing responses to standard-of-care chemotherapy and immunotherapy. The goal of this proposal is to investigate how the microbiome alters immunity in the tumor microenvironment. To achieve this goal, we have developed an orthotopic mouse model of PDAC. Our preliminary data demonstrate that AhR is critical for tumor growth and specific metabolites produced by Lactobacillus species drive macrophage suppressive function and suppress T cell inflammatory maturation. In the current proposal, we will mechanistically investigate how the modulation of macrophage function by AhR occurs in the tumor microenvironment. We will then examine the prediction that blocking AhR will improve tumor responses to gemcitabine and checkpoint inhibitor therapy, and finally we will test predictions generated in the mouse models in human macrophages and examine the correlation between the microbiome, AhR activity, and survival in PDAC patients. The experiments outlined in this proposal will establish important biologic principles and provide a new mechanistic link between microbiome:tumor interactions that fosters growth and metastasis. Ultimately, the mechanisms and paradigms we reveal have the potential to lead to new strategies to treat PDAC and significantly impact clinical outcomes for this terrible disease.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE Pancreatic cancer is one of the most lethal forms of cancer with 5-year survival rates of 7%. Our preliminary data suggest a key factor driving pancreatic tumor progression is the profound immune suppression in tumors driven by gut micro biome-produced metabolites. In this application we predict interfering with this gut-tumor axis will cause the tumors to become inflamed reducing growth and spread rendering pancreatic cancer sensitive to therapy. This project has the potential to completely change our understanding of the microbiome and how it influences immunity. Likewise, lessons learned from this project will enhance our understanding of tumor- gut interactions that will provide new prognostic tools and therapeutic targets.