Modular engineered outer membrane vesicles for synergistic cancer immunotherapy via PD-L1 blockade and epigenetic...

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Immune checkpoint inhibitors (ICIs) show promise in advanced melanoma but face limitations due to resistance and low response rates.
• Developing novel drug delivery systems is crucial to enhance the efficacy of combination immunotherapies for melanoma.

Purpose of the Study:

• To engineer a bacterial outer membrane vesicle (OMV) platform for co-delivery of a PD-1/PD-L1 inhibitor (D-PPA1 peptide) and zebularine.
• To evaluate the efficacy of the OMV-based co-delivery system (OMV@PPA/Zeb) in a melanoma mouse model.

Main Methods:

• SpyCatcher-engineered OMVs were utilized for encapsulating D-PPA1 peptide and zebularine.
• The OMV@PPA/Zeb system's effects on PD-1/PD-L1 interactions and melanoma-associated antigen expression were assessed.
• Tumor growth, systemic toxicity, and immune cell populations (CD8+ T cells and Tregs) were analyzed in a subcutaneous melanoma mouse model.

Main Results:

• OMV@PPA/Zeb effectively blocked PD-1/PD-L1 interactions and increased melanoma-associated antigens.
• The system significantly suppressed tumor growth in mice without causing systemic toxicity.
• OMV@PPA/Zeb enhanced CD8+ T cell infiltration and activation while reducing regulatory T cells in the tumor microenvironment.

Conclusions:

• The engineered OMV platform provides an effective strategy for combination immunotherapy in advanced melanoma.
• Co-delivery of PD-1/PD-L1 inhibitors and epigenetic regulators via OMVs potentiates anti-tumor immune responses.
• This modular OMV-based approach holds potential for treating various advanced tumors.