| Literature DB >> 35139353 |
Kebria Hezaveh1, Rahul S Shinde1, Andreas Klötgen2, Marie Jo Halaby1, Sara Lamorte1, M Teresa Ciudad1, Rene Quevedo1, Luke Neufeld3, Zhe Qi Liu3, Robbie Jin3, Barbara T Grünwald4, Elisabeth G Foerster5, Danica Chaharlangi6, Mengdi Guo3, Priya Makhijani3, Xin Zhang1, Trevor J Pugh7, Devanand M Pinto8, Ileana L Co9, Alison P McGuigan10, Gun Ho Jang11, Rama Khokha12, Pamela S Ohashi3, Grainne M O'Kane13, Steven Gallinger14, William W Navarre6, Heather Maughan15, Dana J Philpott5, David G Brooks3, Tracy L McGaha16.
Abstract
The aryl hydrocarbon receptor (AhR) is a sensor of products of tryptophan metabolism and a potent modulator of immunity. Here, we examined the impact of AhR in tumor-associated macrophage (TAM) function in pancreatic ductal adenocarcinoma (PDAC). TAMs exhibited high AhR activity and Ahr-deficient macrophages developed an inflammatory phenotype. Deletion of Ahr in myeloid cells or pharmacologic inhibition of AhR reduced PDAC growth, improved efficacy of immune checkpoint blockade, and increased intra-tumoral frequencies of IFNγ+CD8+ T cells. Macrophage tryptophan metabolism was not required for this effect. Rather, macrophage AhR activity was dependent on Lactobacillus metabolization of dietary tryptophan to indoles. Removal of dietary tryptophan reduced TAM AhR activity and promoted intra-tumoral accumulation of TNFα+IFNγ+CD8+ T cells; provision of dietary indoles blocked this effect. In patients with PDAC, high AHR expression associated with rapid disease progression and mortality, as well as with an immune-suppressive TAM phenotype, suggesting conservation of this regulatory axis in human disease.Entities:
Keywords: T cells; aryl hydrocarbon receptor; immune suppression; immunotherapy; indoles; macrophage; metabolism; microbiome; pancreatic cancer; tumor microenvironment
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Year: 2022 PMID： 35139353 PMCID： PMC8888129 DOI： 10.1016/j.immuni.2022.01.006
Source DB: PubMed Journal: Immunity ISSN： 1074-7613 Impact factor: 31.745