Abstract
Microbial metabolites promote pancreatic tumor growth through effects on macrophage polarization.
Major Finding: Microbial metabolites promote pancreatic tumor growth through effects on macrophage polarization.
Concept: Protumor macrophage polarization is influenced by a receptor that senses tryptophan-derived indoles.
Impact: This work reveals how the gut microbiome can suppress antitumor immunity in pancreatic cancer.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by a complex tumor microenvironment (TME) that supports tumor growth and suppresses antitumor immunity. Previous studies have suggested that the PDAC TME may be influenced by the host microbiome, which performs many important functions, including conversion of dietary amino acids into metabolites that can modulate the immune system. The aryl hydrocarbon receptor (AhR), known to promote an immune-suppressive phenotype in tumor-associated macrophages (TAM), can be activated upon binding of indoles, which are products of tryptophan metabolism. To investigate whether microbe-mediated AhR activation is a mechanism of TAM-driven immune suppression in PDAC, Hezaveh, Shinde, and colleagues orthotopically injected mice with a PDAC organoid line derived from Trp53+/LSL-R172HKras+/LSL-G12DPdx1-Cre mice and found, compared to normal resident macrophages, that TAMs displayed increased AhR activity. Genetic deletion of Ahr in macrophages promoted inflammatory polarization of TAMs while increasing infiltration and activation of intratumoral CD8+ T cells. Pharmacologic inhibition of AhR recapitulated these effects and extended survival in combination with immune checkpoint blockade. To determine the contribution of bacterial metabolism, tumor-bearing mice were treated with broad-spectrum antibiotics, which significantly lessened tumor weight, and colonization of germ-free mice with the indole-producing bacteria Lactobacillus murinus and Lactobacillus reuteri supported the role of these species in increasing tumor burden. The removal of dietary tryptophan reduced tumor size and increased activation of TAMs and CD8+ T cells, whereas dietary supplementation of indoles rescued this effect, supporting the concept that microbial metabolism of tryptophan produces indoles that trigger AhR signaling in TAMs to drive immune suppression. In agreement with this model, indole-producing bacteria were enriched in the local tumor microbiomes of patients with PDAC who survived less than 5 years after resection when compared to long-term survivors (>5 years survival after resection), and low AHR expression below a threshold value was associated with improved overall survival. In summary, this work highlights a key interaction between the host microbiome and TME that suppresses antitumor immunity, with implications for therapeutic interventions in PDAC.
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