The induction of CD8+ cytotoxic T lymphocytes (CTL) is vital in the immune response to tumour growth, and the presence of tumour-infiltrating CTL correlates with positive prognoses. Immunotherapies aim to either induce potent anti-tumour immune responses through vaccination, or to increase the numbers of tumour-specific CTL in patients and/or strengthen their effector functions against tumours. However, within the tumour microenvironment (TME) many immunosuppressive mechanisms operate to prevent cytotoxic activity amongst CD8+ tumour-infiltrating T lymphocytes (TIL). Previous studies have shown that loss of CTL function within the TME is associated with the influx of large numbers of FoxP3+CD4+ regulatory T cells expressing ectoenzymes CD39 and CD73 that catalyse stepwise adenosine production. Other studies also showed that there is an upregulation in the expression of coinhibitory receptors (CIRs) amongst CD8+ TIL compared with CTL. We hypothesised that production of immunosuppressive adenosine may also contribute to CTL effector function loss through upregulation of CIRs, thus promoting continued tumour growth. Studies detailed in this thesis were carried out in order to identify changes in the expression patterns of the CIRs PD1, TIM3, TIGIT and LAG3 and in CTL proliferation amongst tumour-specific CD8+ T cells in the presence of 5′-(N-Ethylcarboxamido) adenosine (NECA), an adenosine receptor agonist; and to test the ability of a novel vaccine strategy using scaffold proteins called Self-Assembling peptide caGEs (SAGE) to deliver tumour-specific peptides to stimulate CD8+ T cell proliferation in vivo. The data show that NECA did not affect expression patterns of PD1, TIM3, TIGIT and LAG3 during CTL priming in vitro. However, we do show that SAGE constructs are capable of driving strong proliferative responses of CTLs in vivo. These findings provide further insight into the immunosuppressive mechanisms within the TME as well the immunotherapeutic potential of using novel SAGE-conjugated peptides to stimulate anti-tumour CTL responses in vivo.
|Date of Award||19 Mar 2019|
- The University of Bristol
|Supervisor||David J Morgan (Supervisor)|