Modulating tumor immunity using advanced microbiome therapeutics producing an indole metabolite
Troels Holger Vaaben, Ditte Olsen Lützhøft, Andreas Koulouktsis, Ida Melissa Dawoodi, Camilla Stavnsbjerg, Lasse Kvich, Ismail Gögenür, Ruben Vazquez-Uribe, Morten Otto Alexander Sommer
Abstract
The gut microbiome has emerged as a key player in modulating immune responses against cancer, suggesting that microbial interventions can enhance treatment outcomes. Indole metabolites produced by probiotic bacteria activate the aryl hydrocarbon receptor (AhR), a transcription factor important for immune cell regulation. Cancer patients with high plasma concentrations of these metabolites have shown improved survival. Building on these findings, we have engineered Escherichia coli Nissle 1917 to produce the AhR agonist indole-3-acetic acid. Delivery of indole-3-acetic acid by tumor-colonizing bacteria changes the tumor microenvironment in a murine model, significantly increasing levels of CXCL9 and IFN-γ and elevating tumor-infiltrating T-cell abundance and activation. Treatment with our engineered strain inhibits tumor growth, improves survival in syngeneic tumor models, and leads to long-lasting immunity in a tumor rechallenge experiment. Further investigation indicates that this immune modulation is driven by the direct activation of AhR by indole-3-acetic acid, leading to differential cytokine expression and a shift in immune cell composition within the tumor. This study highlights the importance of microbial metabolites in immune modulation and supports exploring microbiome-based therapies in oncology.