Microbiome-Driven Tryptophan Metabolism Suppresses Immunity in the Pancreatic Tumor Microenvironment by Activation of the Aryl Hydrocarbon Receptor

The microbiome exerts profound influence on immunity and survival in pancreatic cancer. However, links between the microbiome and tumor immunity remain poorly understood. The Aryl Hydrocarbon Receptor (AhR) is a sensor of metabolic products of tryptophan metabolism and is a potent modulator of immunity. Here we demonstrate AhR is activated in tumor associated macrophages (TAMs) and is fundamental for acquisition of a suppressive phenotype. AhR activity was dependent on tryptophan derived indoles and removal of tryptophan from the diet or depletion of the microbiome significantly reduced AhR activity in TAMs. Importantly we identified Lactobacillus species in the microbiome that impacted AhR function, T cell activation, and tumor burden by production of indoles. Moreover, we found AhR transcriptional signatures were associated with reduced CD8+ T cell infiltration and worse outcomes in pancreatic cancer patients. Thus, AhR is a therapeutically targetable central node linking the microbiota, immune suppression, and PDAC progression.