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Title: An in vitro study investigating the effect of Bacillus Calmette-Guerin on V62+ T-cell responses to tumour cells
Author: Fenn, Joe
ISNI:       0000 0004 8502 879X
Awarding Body: St George's, University of London
Current Institution: St George's, University of London
Date of Award: 2019
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V62+ cells are a subset of unconventional T-cells which comprise about 1 in 40 memory T-cells in the adult peripheral blood. Their TCR is specialized to recognise small pyrophosphate antigens (pAgs) in the context of the presenting molecule butyrophilin 3A1 (BTN3A1). pAgs, such as isopentenyl pyrophosphate (IPP), are produced endogenously and often exist at elevated levels in malignantly transformed cells as a result of metabolic dysregulation, hence V62+ cells are able to recognise and kill some cancerous cells. In tumour cells in which IPP production is not dysregulated, its overproduction can be induced using bisphosphonate drugs such as Zoledronic acid (ZA). This has led to a number of clinical trials investigating methods to harness the anti-tumour properties of V62+ cells to develop novel cancer immunotherapies. Other pAgs, such as (E)-4-hydroxy-3-methyl-but-2-enyl-pyrophosphate (HMBPP) are produced by a range of bacteria during normal metabolism. The mycobacterium Bacillus Calmette-Guerin (BCG) is an example of a bacterium that produces HMBPP, a feature which causes BCG-infected cells to be susceptible to recognition and killing by V62+ cells. The ability of V62+ cells to respond to both malignant cells and BCG led to the hypothesis that BCG could be used therapeutically to stimulate V52+ cells in order to potentiate their anti-tumour responses. Experiments presented in this thesis aimed to characterise V62+ cell phenotypic markers, investigate their modulation during expansion of V62+ cells using ZA, and assess associations between phenotype and anti-tumour responses. Results showed that upregulation of CD56 occurred during expansion and that expression of this molecule was associated with enhanced cytotoxic responses by VS2+ cells. Methods to expand V62+ cells using BCG were optimised and a model of BCG infection was established. These methods were used to compare the responses of ZA-expanded and BCG-expanded V62+ cells to both tumour cells and BCG-infected cells. The results showed that BCG-expanded V62+ cells elicited more potent anti-tumour responses than ZA-expanded cells to both targets as assessed by cytotoxicity and cytokine release assays. These results support the idea that BCG could be useful therapeutically to induce anti-tumour V52+ cell responses.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available