Modulating tumor immunity using advanced microbiome therapeutics producing an indole metabolite

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.