Tomasi, Michele (2018) Bacterial outer membrane vesicles (OMVs) as a platform for personalized cancer vaccines. PhD thesis, University of Trento.
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Cancer is the second leading cause of death worldwide. Tumor cells contain several mutations that can generate neoepitopes, targets of an effective anti-cancer T cell response. Increasing evidence demonstrated that cancer vaccines targeting neoepitopes are effective and safe both in preclinical models and human patients. Bacterial Outer Membrane Vesicles (OMVs) are naturally produced by all Gram-negative bacteria. They contain several Microbe-Associated-Molecular Patterns (MAMPs), crucial for stimulating innate immunity and promoting adaptive immune responses. The ability to engineer OMVs with cancer epitopes together with their unique adjuvanticity and safety make them a particularly interesting vaccine platform. In this study, we have demonstrated that immunization of mice with OMVs activate both innate and adaptive immunity and induce a Th1 immune response, fundamental for an effective cancer vaccine. OMV immunization also caused upregulation of genes involved in MAMPs detection and signal transduction, a central component of the inflammasome and pro-inflammatory cytokines. OMV vaccination induced an upregulation of Th1 key transcription factor and cytokines, while inducing a downregulation of transcription factor and cytokines associated to Th2 response. Moreover, cytokines released by activated macrophages, DCs, T cells and natural killer (NK) cells were induced by OMV vaccination, together with a key chemokine and a protein for immune cell recruitment and adhesion, respectively. We have successfully engineered OMVs on the surface and in the lumen with OVA(257-264) CD8 T cell model epitope. These OVA-engineered OMVs induced a high percentage of OVA(257-264) specific CD8 T cells and protected mice from OVA-expressing tumors. We have shown that OMVs engineered with a tumor specific antigen (TSA) induced a protective response and promoted a significant recruitment of CD4 and CD8 T cells into tumors, while reducing both CD4 regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). We have also shown in the same mouse model that vaccination with OMVs engineered with two TSAs have a synergistic protective activity in controlling tumor growth. Finally, we have demonstrated that therapeutic OMV vaccines targeting five different neoepitopes protect mice from tumor growth. Taken together, our results show that OMVs are a promising platform for effective personalized cancer vaccines.
|Item Type:||Doctoral Thesis (PhD)|
|Doctoral School:||Biomolecular Sciences|
|Subjects:||Area 05 - Scienze biologiche > BIO/11 BIOLOGIA MOLECOLARE|
|Repository Staff approval on:||10 May 2018 15:33|
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