Tryptophan-derived microbial metabolites activate the aryl hydrocarbon receptor in tumor-associated macrophages to suppress anti-tumor immunity

• DOI: 10.1016/j.immuni.2022.01.006
• Publication Date: 2022-02-08T15:41:40Z
• Authors: Kebria Hezaveh; Rahul S. Shinde; Andreas Klötgen; Marie Jo Halaby; Sara Lamorte; M. Teresa Ciudad; Rene Quevedo; Luke Neufeld; Zhe Qi Liu; Robbie Jin; Barbara T. Grünwald; Elisabeth G. Foer...; Danica Chaharlangi; Mengdi Guo; Priya Makhijani; Xin Zhang; Trevor J. Pugh; Devanand M. Pinto; Ileana L. Co; Alison P. McGuigan; Gun Ho Jang; Rama Khokha; Pamela S. Ohashi; Grainne M. O’Kane; Steven Gallinger; William W. Navarre; Heather Maughan; Dana J. Philpott; David G. Brooks; Tracy L. McGaha
• Keywords: Indoles; aryl hydrocarbon receptor; Microbiota; pancreatic cancer; T cells; Tryptophan; microbiome; macrophage; indoles; CD8-Positive T-Lymphocytes; Prognosis; Pancreatic Neoplasms; Mice; Lymphocytes, Tumor-Infiltrating; Receptors, Aryl Hydrocarbon; Tumor-Associated Macrophages; Immune Tolerance; Tumor Microenvironment; tumor microenvironment; Animals; Humans; immunotherapy; immune suppression; metabolism; Carcinoma, Pancreatic Ductal

The aryl hydrocarbon receptor (AhR) is a sensor of products tryptophan metabolism and potent modulator immunity. Here, we examined the impact AhR in tumor-associated macrophage (TAM) function pancreatic ductal adenocarcinoma (PDAC). TAMs exhibited high activity Ahr-deficient macrophages developed an inflammatory phenotype. Deletion Ahr myeloid cells or pharmacologic inhibition reduced PDAC growth, improved efficacy immune checkpoint blockade, increased intra-tumoral frequencies IFNγ+CD8+ T cells. Macrophage was not required for this effect. Rather, dependent on Lactobacillus metabolization dietary to indoles. Removal TAM promoted accumulation TNFα+IFNγ+CD8+ cells; provision indoles blocked In patients with PDAC, AHR expression associated rapid disease progression mortality, as well immune-suppressive phenotype, suggesting conservation regulatory axis human disease.