Abstract
Gram-negative bacteria actively secrete outer membrane vesicles, spherical nano-meter-sized proteolipids enriched with outer membrane proteins, to the surroundings. Outer membrane vesicles have gained wide interests as non-living complex vaccines or delivery vehicles. However, no study has used outer membrane vesicles in treating cancer thus far. Here we investigate the potential of bacterial outer membrane vesicles as therapeutic agents to treat cancer via immunotherapy. Our results show remarkable capability of bacterial outer membrane vesicles to effectively induce long-term antitumor immune responses that can fully eradicate established tumors without notable adverse effects. Moreover, systematically administered bacterial outer membrane vesicles specifically target and accumulate in the tumor tissue, and subsequently induce the production of antitumor cytokines CXCL10 and interferon-γ. This antitumor effect is interferon-γ dependent, as interferon-γ-deficient mice could not induce such outer membrane vesicle-mediated immune response. Together, our results herein demonstrate the potential of bacterial outer membrane vesicles as effective immunotherapeutic agent that can treat various cancers without apparent adverse effects.
Highlights
Gram-negative bacteria actively secrete outer membrane vesicles, spherical nano-metersized proteolipids enriched with outer membrane proteins, to the surroundings
To avoid possible adverse effects due to bacterial endotoxin lipopolysaccharide, we used Gram-negative bacterial outer membrane vesicles (OMVs) derived from genetically modified Escherichia coli, whose gene encoding lipid A acyltransferase, the lipid component of lipopolysaccharide, had been inactivated (E. coli msbB−/−, ΔmsbB)[23,24,25]
Gram-negative and Gram-positive bacterial extracellular vesicles are found in various biological fluids including the blood, urine, saliva, and feces, allowing new insight in the design of both personalized and universal cancer vaccines using commensal bacterial extracellular vesicles[35, 36]
Summary
Gram-negative bacteria actively secrete outer membrane vesicles, spherical nano-metersized proteolipids enriched with outer membrane proteins, to the surroundings. Our results demonstrate the potential of bacterial outer membrane vesicles as effective immunotherapeutic agent that can treat various cancers without apparent adverse effects. Bacterial outer membrane vesicles (OMVs), known as extracellular vesicles, are naturally produced from all Gramnegative bacteria and have nano-sized lipid-bilayered vesicular structures composed of various immunostimulatory components[13,14,15,16] This acellular bacterial OMV is one of the cuttingedge immunostimulatory agents recognized by many scientists as candidate vaccines and delivery vehicles[17,18,19]. The results in this study demonstrate the great potential of bacterial OMVs as novel therapeutic agents that can trigger effective antitumor response against various cancers without notable adverse effects
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