Targeting the Adenosine-Mediated Metabolic Immune Checkpoint with Engineered Probiotic for Enhanced...

Area of Science:

• Oncology
• Immunology
• Microbiology

Background:

• Cancer immunotherapy efficacy is limited by the immunosuppressive tumor microenvironment (TME).
• Adenosine accumulation in the TME suppresses anti-tumor immune cell function via cAMP signaling.
• Targeting adenosine metabolism is a potential strategy to overcome immune suppression.

Purpose of the Study:

• To develop a genetically engineered probiotic for in situ adenosine degradation within the TME.
• To evaluate the efficacy of engineered Escherichia coli Nissle 1917 expressing adenosine deaminase in a colorectal cancer model.
• To assess the impact of the engineered probiotic on immune cell infiltration and phenotype within the TME.

Main Methods:

• Genetic engineering of Escherichia coli Nissle 1917 to express surface adenosine deaminase under hypoxic conditions.
• Administration of engineered probiotic to subcutaneous and orthotopic mouse colorectal cancer models.
• Analysis of immune cell populations (macrophages, T cells) and cytokine profiles in tumor tissues.
• Assessment of synergistic effects with low-dose doxorubicin chemotherapy.

Main Results:

• Engineered probiotic successfully targeted tumors and degraded adenosine to inosine.
• Significant increase in anti-tumor immune cell infiltration, including effector T cells.
• Modulation of the TME, characterized by a shift from M2-like to M1-like macrophages.
• Synergistic anti-tumor effects observed when combined with low-dose doxorubicin.

Conclusions:

• Genetically engineered probiotics can effectively remodel the immunosuppressive TME by metabolizing adenosine.
• This approach enhances anti-tumor immune responses and potentiates chemotherapy efficacy.
• Engineered probiotics represent a promising novel strategy for improving cancer immunotherapy.