Nicklin, Alicia D. (2024) Developing Bifidobacterium-based therapeutics to improve cancer outcome and prevent occurrence. Doctoral thesis, University of East Anglia.
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Abstract
Historically, the use of microorganisms for immune modulation has been explored, but their role in cancer immunotherapy is still emerging. Recent studies, both human and preclinical, have emphasised the importance of specific gut microbes in cancer progression, including cancers outside the gastrointestinal (GI) tract. Specifically, Bifidobacterium, recognised for its immunogenic properties, has been linked to anti-tumour responses including boosting existing treatment efficacy.
To investigate the anti-tumour effects of Bifidobacteria, novel strains (or PBS as control) were orally administered to tumour-burdened mice in a range of breast cancer models. Several, but not all, strains significantly inhibited tumour growth in a PyMT-Bo1 model. One strain appeared to operate through a CD8+ T cell-driven mechanism, suggesting that strain discrepancies influence host responses. Focusing on Bif210, there were minimal changes in the caecal metagenome and metabolome after oral administration, likely due to Bif210’s presence in the GI tract being transient. Taken together, with the observation that the tumours were sterile, Bif210 likely interacts with GI immune cells, modifying systemic and tumour-associated immune responses. While Bif210 increased circulatory CD8+ T memory cells, it did not offer protection for metastasis in murine models, yet potentially could act as a chemopreventive agent.
To further unlock the immunotherapeutic potential of Bif210, its extracellular vesicles (BEVs) were investigated. Intravenous administration of Bif210 BEVs to C57BL/6 mice significantly reduced melanoma tumour volumes compared to controls. Mechanistically, BEVs increased the infiltration of tumour-associated Ly6G granulocytes. In vivo Ly6G depletion highlighted the contrasting roles of Ly6G granulocytes to melanoma progression, it has therefore been proposed that Bif210 BEVs polarise these cells to an anti-tumourigenic phenotype.
Harnessing specific microbiota and microbial-derived products to modulate tumour immune responses offers a novel approach to potentially complement conventional cancer therapies. To develop this clinically, further research to evaluate efficacy in humans is imperative.
Item Type: | Thesis (Doctoral) |
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Faculty \ School: | Faculty of Science > School of Biological Sciences |
Depositing User: | Chris White |
Date Deposited: | 09 Jan 2025 09:48 |
Last Modified: | 09 Jan 2025 09:48 |
URI: | https://ueaeprints.uea.ac.uk/id/eprint/98129 |
DOI: |
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