Immunisation is the single most successful medical intervention to date. With the improved understanding of cancer immunity, cancer vaccines have quickly become weapons to be honed in the fight against cancer. The low immunogenicity of malignant cells hampers cancer immunotherapies. Cancer vaccines promise to overcome this problem.Outer membrane vesicles (OMVs) are spherical structures shed from all gram-negative bacterial outer membranes. Currently, OMV-based vaccines focus on infectious disease. There are gaps in their use as cancer antigen delivery vehicles for cancer vaccines. Due to their adjuvanticity and simplicity for genetic engineering, OMVs have great potential as a cancer vaccine platform. Here the aim is to show that it is possible to express an antibody derived single-chain variable fragment (scFv), specific for dendritic cell receptor DEC205, on the surface of OMVs using a bacterial protein as a carrier. Then demonstrate OMVs can be used to elicit good CD8+ T cell responses. And finally show that their adjuvant and delivery vehicle properties lend them for use in in situ cancer vaccination.I have shown we can engineer OMVs to express a functional scFv specific for the dendritic cell receptor DEC205 using a carrier. And that our proteome-minimised OMVs improved surface expression of the scFv fusion protein. The expression of the dendritic cell specific scFv increases internalisation of OMVs in dendritic cells. Importantly, this demonstrates an effective method for modifying OMV interaction with antigen presenting cells. Moreover, our OMVs, without additional dendritic cell targeting, are efficient vehicles for antigen delivery and can be used to elicit strong CD8+ T cell responses. Finally, we show that our proteome-minimised OMVs alone induce anti-tumour immunity when injected intratumorally. Additionally, in the presence of tumour-specific neoepitopes we elicit an improved anti-tumour response.The flexibility of OMVs both as adjuvants and vehicles for antigen delivery means they make a versatile vaccine platform, which can be fine-tuned using the techniques demonstrated.
Investigating antigen delivery and presentation of OMV-based cancer vaccines / Isaac, Samine Jessica. - (2020 Oct 27), pp. 1-126.
|Titolo:||Investigating antigen delivery and presentation of OMV-based cancer vaccines|
|Anno di pubblicazione:||2020-10-27|
|Struttura:||Dipartimento di Biologia Cellulare, Computazionale e Integrata - CIBIO|
|Corso di dottorato:||Biomolecular Sciences|
|Tesi in cotutela:||no|
|Digital Object Identifier (DOI):||10.15168/11572_277831|
|Appare nelle tipologie:||08.1 Tesi di dottorato (Doctoral Thesis)|
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|Samine Isaac PhD Thesis.pdf||Samine J. Isaac PhD Thesis||Tesi di dottorato (Doctoral Thesis)||Tutti i diritti riservati (All rights reserved)||Embargo: 27/10/2022|