Abstract
Prostate cancer is the second most common cancer in men worldwide. Although a number of prostate-specific antigens exist, immunotherapies have yet to become a standard of care for prostate cancer. Innate-like T-cells are being explored as targets for anti-cancer immunotherapies. In humans, they comprise approximately 10% of circulating T-cells and recognize non-peptide antigens presented on non-classical major histocompatibility molecules.
In this thesis I design a platform of assays to evaluate the number and function of three innate-like T-cell subsets: invariant natural killer T, mucosal associated invariant T and Vgamma9Vdelta2 T-cells. I apply this platform of assays to samples from men with prostate cancer and age- and sex-matched controls, identifying reduced MAIT-cell function in men with prostate cancer which was associated with upregulation of the inhibitory receptor PD-1.
To inform the co-application of innate-like T-cell-based immunotherapies and checkpoint blockade, I then evaluated the expression of the checkpoint inhibitory receptors PD-1, LAG-3 and CTLA-4 on innate-like T-cell function. This demonstrated greater expression of these markers on resting and stimulated innate-like T-cells. Despite this, I was not reliably able to demonstrate an effect of antagonistic monoclonal antibodies against PD-1 and LAG-3 on healthy donor ILT-cell function, or in patients with melanoma receiving systemic anti-PD-1 treatment (pembrolizumab). Lastly, using the PC3 cell line as a model of human prostate cancer, I was able to show that stimulation of MAIT-cells enhanced suppression of tumour cell growth in an MR-1-dependent manner. This cytotoxicity could be enhanced by an anti-PD-1.
In conclusion, this thesis supports the potential development of innate-like T-cell-based immunotherapy for prostate cancer, including in combination with checkpoint blockade.