Regulation of anti-tumour immunity by GSK-3, a potential target for immunotherapy

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The main purpose of this project is to study the role of Glycogen synthase kinase-3 (GSK-3) in the immune response. Previous work has shown that the anti-tumour activity of cytotoxic lymphocytes (namely CD8+ T cells and natural killer [NK] cells) can be enhanced by the inhibition of GSK-3. However, due to GSK-3 being largely ubiquitous in many tissues, this has created difficulties in drug design. Therefore, with the use of genetic knockout models, this project aims to uncover the mechanism behind GSK-3 regulation of anti-tumour immunity and identify other targets linked to this pathway which may be more suitable candidates for immunotherapy.Identified targets will be validated in vitro using immunological and biochemical approaches and their impact on modulating these pathways on tumour recognition and killing will be assessed. It will then be determined whether these pathways downstream of GSK-3 are themselves druggable and they will be evaluated for their potential as therapeutic targets for future development.Identified targets of GSK-3 will be analysed in CD8+ T cells and NK cells using immunological (e.g. tumour killing assays, cytokine release, immune checkpoint expression) and biochemical/genetic methods (enzyme assays, gene and protein expression); these approaches include laboratory techniques such as immune cell purification from blood/tissue, ELISAs and flow cytometry, western blotting, and quantitative RT-PCR. Bioinformatics will also form part of the project, including gene-set enrichment analysis (GSEA), network analysis and statistical methods to compare and analyse transcriptome data from laboratory models with datasets derived from cancer patient cohorts.