Bacterial Membrane Vesicles as Heteroantigen Reservoirs for Potentiated Colorectal Cancer Immunotherapy

Area of Science:

• Oncology
• Immunology
• Biotechnology

Background:

• Cancer immunotherapy, particularly immune checkpoint blockade (ICB), faces limitations due to insufficient neoantigen presentation.
• Neoantigen vaccines are costly and challenged by tumor heterogeneity.
• Heteroantigen presentation offers a viable alternative strategy to boost immunotherapy efficacy.

Purpose of the Study:

• To develop bacterial membrane vesicles as reservoirs for heteroantigens and siRNA targeting PD-L1 (siPD-L1).
• To evaluate the synergistic therapeutic effect of combined heteroantigen presentation and ICB.
• To assess the efficacy of this approach in preclinical cancer models, including colorectal cancer.

Main Methods:

• Hyaluronic acid (HA)-modified bacterial membrane vesicles (HLGV) were engineered to carry heteroantigens and siPD-L1.
• HLGV facilitated intracellular release of cargo via endosomal membrane fusion, enabling MHC class I presentation and PD-L1 silencing.
• HLGV@siPD-L1, encapsulated in chondroitin sulfate hydrogel microspheres (HEBV@siPD-L1), was administered peritumorally and via oral gavage for colorectal cancer models.

Main Results:

• Peritumoral administration of HLGV@siPD-L1 significantly inhibited subcutaneous CT-26 tumors and distant metastases.
• Oral gavage of HEBV@siPD-L1 suppressed orthotopic colorectal cancer growth by 91.6%.
• The treatment increased the infiltration of macrophages and CD8+ T cells, indicating enhanced antitumor immune responses.

Conclusions:

• Bacterial membrane vesicles serve as effective heteroantigen reservoirs to activate antitumor immunity.
• The combination of heteroantigen presentation and ICB via bacterial membrane vesicles synergistically enhances therapeutic efficacy.
• This strategy holds significant potential for advancing cancer immunotherapy, particularly for colorectal cancer treatment.