Modified bacterial outer membrane vesicles induce autoantibodies for tumor therapy

Abstract

Using monoclonal antibodies to block tumor angiogenesis has yielded effective antitumor effects. However, this treatment method has long cycles and is very expensive; therefore, its long-term and extensive application is limited. In this study, we developed a nanovaccine using bacterial biomembranes as carriers for antitumor therapy. The whole basic fibroblast growth factor (BFGF) molecule (154 amino acids (aa)) was loaded onto bacterial outer membrane vesicles (OMVs) using gene recombination technology. The strong adjuvant effect of OMVs was used to induce the host to produce anti-BFGF autoantibodies. We proved that persistent anti-BFGF autoantibodies can be induced in mice after only 3 immunizations to antagonize BFGF functions. The effects included multiple tumor suppression functions, including inhibition of tumor angiogenesis, induction of tumor cell apoptosis, reversal of tumor immune barriers, and promotion of tumor-specific cytotoxic T lymphocytes (CTLs), eventually causing tumor regression. We confirmed that bacterial biomembranes can be used as a vaccine delivery system to induce the production of antibodies against autoantigens, which may be used for tumor therapy. This study expands the application fields of bacterial biomembrane systems and provides insight for tumor immunotherapy other than monoclonal antibody technology. STATEMENT OF SIGNIFICANCE: In this study, we proved that bacteria-released outer membrane vesicles (OMVs) modified via genetic engineering can be used as a vaccine carrier to break autoimmune tolerance and induce the body to produce autoantibodies to antagonize pathological molecules and block pathological signaling pathways for tumor therapy. OMVs naturally released by bacteria were used to successfully load the full-length BFGF protein (154 aa). We proved that persistent anti-BFGF autoantibodies can be induced in tumor-bearing mice after only 3 immunizations to effectively inhibit tumors. Furthermore, the production of these antibodies successfully inhibited tumor angiogenesis, promoted tumor cell apoptosis, reversed the tumor immunosuppressive microenvironment, increased the cytotoxic T lymphocyte (CTL) reaction, and eventually inhibited tumor growth.

Keywords: Antiangiogenesis; Autoantibody; Basic fibroblast growth factor; Biomembrane; Outer membrane vesicle; Tumor immunotherapy.