Developing microbial biotherapeutics for the immunotherapy of cancer

Price, Christopher A. (2023) Developing microbial biotherapeutics for the immunotherapy of cancer. Doctoral thesis, University of East Anglia.

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Abstract

Over recent decades, the microbial communities of the gut have been validated as powerful regulators of human immunity and cancer. Both animal and human studies have shown that the supplementation with specific beneficial gut bacteria can significantly improve outcomes, yet no bacteria-based drugs have yet been successfully translated to the clinic. One of the major challenges facing the field, is a lack of understanding of the detailed molecular mechanisms of action which govern efficacy, both in the context of bacterial active compound production and the host antitumour response. This lack of understanding prevents the rational use of responsepredicting biomarkers, which in turn prevents proper patient stratification and leads to inconsistent clinical responses. Additionally, poor characterisation of the key active compounds produced by therapeutic bacteria prevents the isolated administration of functional ingredients and thus requires the utilisation of live bacteria, whose activity are inherently dictated by individual host conditions (e.g., diet, abundance of competing bacteria, antibiotic use). The research presented here shows a mechanism-focused approach to bacterial drug discovery, focusing on the commensal Bifidobacterium and Bacteroides, which have received significant attention for cancer-protective properties. Specifically, we show that Bifidobacterium, as a genus, are broadly protective against pre-clinical breast cancer models through a range of unique, strain-specific mechanisms. We show for the first time, that a strain of Bifidobacterium pseudocatenulatum (LH663) activates host CD8+ T cell anti-tumour immunity against the major subtypes of breast cancer. We validate that this effect is specifically mediated by cell surface exopolysaccharide (EPS), which functions mechanistically to enhance the activity of CD8+-specific dendritic cells. Finally, we also demonstrate the novel utility of Bacteroides thetaiotaomicron outer membrane vesicles (OMVs) as anticancer therapeutic agents against pre-clinical melanoma.

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Science > School of Biological Sciences
Depositing User:	Nicola Veasy
Date Deposited:	25 Jan 2024 10:36
Last Modified:	25 Jan 2024 10:36
URI:	https://ueaeprints.uea.ac.uk/id/eprint/94253
DOI:

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