Regulation of anti-tumour immunity by GSK-3; a potential target for immunotherapy 2732

Abstract Description Immunotherapy has improved cancer treatment in recent decades, which harnesses the immune system to tackle cancer. However, not all cancer patients respond, nor does it cover all cancers, so alternative avenues are required. Glycogen Synthase Kinase 3 (GSK-3) is a widely expressed kinase involved in numerous cellular processes and diseases, including cancer. There are two isoforms, α and β, though their specific roles are not well understood. Small molecule inhibitors against GSK-3 have been tested with varying success. Preclinical work in our lab has demonstrated that inhibiting GSK-3, either chemically or genetically, boosts CD8+ T cell cytolytic properties and reduces immune checkpoint molecules, enhancing tumour clearance in many in-vivo tumour models. Here, we hypothesise that GSK-3 inhibition also enhances NK cell cytolytic activity. We have developed an ex-vivo activation assay to investigate multiple GSK-3 inhibitors in murine NK cells and use mice bearing melanoma tumours with and without GSK-3 inhibitors to further examine NK cells. Furthermore, a novel conditional knockout mouse model has been generated, using a cre-recombinase system to deplete GSK-3 isoforms specifically in NK cells. With inhibitors largely incapable of selectively targeting the isoforms, this approach enables investigation into the effect of each isoform on NK cells and tumour development. Understanding how GSK-3 inhibition slows tumour growth could lead to improved or alternative treatments. Funding Sources Medical Research Council Discovery Medicine North Doctoral Training Partnership MRC Grant MR/V033336/1 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)