Antigen-bearing outer membrane vesicles as tumour vaccines produced in situ by ingested genetically engineered bacteria
Menée à l'aide d'un modèle murin de mélanome avec métastases pulmonaires et d'un modèle murin de tumeur colique sous-cutanée, cette étude met en évidence l'intérêt thérapeutique de bactéries Escherichia coli administrées par voie orale et capables d'exprimer in situ, à la surface des vésicules de la membrane externe et sous le contrôle d'un promoteur induit par l'arabinose, une protéine de fusion combinant un antigène tumoral et la cytolysine A
The complex gastrointestinal environment and the intestinal epithelial barrier constrain the design and effectiveness of orally administered tumour vaccines. Here we show that outer membrane vesicles (OMVs) fused to a tumour antigen and produced in the intestine by ingested genetically engineered bacteria function as effective tumour vaccines in mice. We modified Escherichia coli to express, under the control of a promoter induced by the monosaccharide arabinose, a specific tumour antigen fused with the protein cytolysin A on the surface of OMVs released by the commensal bacteria. In mice, oral administration of arabinose and the genetically engineered E. coli led to the production of OMVs that crossed the intestinal epithelium into the lamina propria, where they stimulated dendritic cell maturation. In a mouse model of pulmonary metastatic melanoma and in mice bearing subcutaneous colon tumours, the antigen-bearing OMVs inhibited tumour growth and protected the animals against tumour re-challenge. The in situ production of OMVs by genetically modified commensal bacteria for the delivery of stimulatory molecules could be leveraged for the development of other oral vaccines and therapeutics.