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Updated: May 23, 2025
In Vivo Augmentation of Gut-Homing Regulatory T Cell Induction
Published on: January 22, 2020
Modulating tumor immunity using advanced microbiome therapeutics producing an indole metabolite
Troels Holger Vaaben1, Ditte Olsen Lützhøft1, Andreas Koulouktsis1
1Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kgs. Lyngby, DK2800, Denmark.
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.
Insights
Engineered bacteria delivering indole-3-acetic acid enhance anti-tumor immunity by activating the aryl hydrocarbon receptor (AhR). This microbiome-based therapy inhibits tumor growth and improves survival, offering a promising approach for cancer treatment.
Area of Science:
- Oncology
- Immunology
- Microbiology
Background:
- The gut microbiome influences immune responses against cancer.
- Microbial indole metabolites activate the aryl hydrocarbon receptor (AhR), impacting immune cell regulation.
- Elevated metabolite levels correlate with improved survival in cancer patients.
Purpose of the Study:
- To engineer bacteria for enhanced anti-tumor immunity.
- To investigate the role of microbial metabolites in modulating the tumor microenvironment.
- To evaluate the therapeutic potential of engineered bacteria in cancer models.
Main Methods:
- Engineered Escherichia coli Nissle 1917 to produce indole-3-acetic acid (an AhR agonist).
- Administered engineered bacteria to a murine tumor model.
- Analyzed changes in the tumor microenvironment, including cytokine levels (CXCL9, IFN-γ) and T-cell populations.
- Assessed tumor growth, survival rates, and long-term immunity through rechallenge experiments.
Main Results:
- Engineered bacteria delivered indole-3-acetic acid, altering the tumor microenvironment.
- Significant increases in CXCL9, IFN-γ, and tumor-infiltrating T-cell abundance and activation were observed.
- Treatment inhibited tumor growth, improved survival in syngeneic models, and induced long-lasting anti-tumor immunity.
- Direct AhR activation by indole-3-acetic acid was identified as the driver of immune modulation.
Conclusions:
- Microbiome-based interventions hold promise for cancer therapy.
- Engineered bacteria producing AhR agonists can enhance anti-tumor immune responses.
- This approach modulates the tumor microenvironment, leading to tumor growth inhibition and improved survival.
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