Glioblastoma Multiforme (GBM) is an incurable form of brain cancer. However, there is now an opportunity to apply the advances in cellular immunotherapies to treat GBM. Natural Killer (NK) cells are cytotoxic lymphocytes that can identify and kill tumour cells. Our collaborative research has characterised the importance of cellular metabolism for sustaining NK cell anti-tumour responses. NK cells present in GBM tumours are largely dysfunctional, presumably the result of an immunosuppressive tumour microenvironment (TME). Our analyses of GBM datasets reveal that GBM tumours contain the machinery to create an environment rich in metabolites (including fatty acids and oxysterols) and proteins (e.g. TGF beta) that potently suppress the metabolism and cytotoxicity of NK cells. Our hypothesis is that the metabolic microenvironment of GBM is a central driver of NK cell dysfunction and a limiting factor for NK cell immunotherapies. Here we bring together the essential expertise and technologies to test this hypothesis and translate discoveries into novel clinical therapeutic approaches. Our primary aim is to establish the nature the suppressive metabolic TME, the presence of inhibitory factors like TGF beta, and to understand how this interferes with the metabolism and function of infiltrating NK cells. The data will guide our secondary aim of developing novel approaches to bolster NK cell metabolism towards enhanced cytotoxic activities with GBM tumours. Spatial imaging techniques will be used to identify and quantitate with single-cell resolution metabolites and lipids by DESI-/MALDI-mass spec imaging (MSI) (Germany) and TGF beta production/signalling components by multiplex immunofluorescence imaging (Belgium) to characterize the spatial distribution of the metabo-lipidome and TGF beta actions within in GBM tumours. Modelling approaches will estimate the relationship between captured metabolites, lipids and TGF beta pathway components and the immunological landscape with respect to NK cells abundance and functionality (Ireland/Germany). Flow cytometry, confocal and electron microscopy (Ireland/Norway), will be used to study the metabolic phenotype of GBM infiltrating NK cells, including mitochondrial structure and function, previously shown to be impaired in NK cells from cancer patients. Using preclinical GBM models we will test NK cell immunotherapeutic approaches with interventions to bolster NK cell metabolism; achieved through genetic engineering of NK cells or antibody meditated blockade of the TGF beta signalling axis or other identified factors (Ireland/Belgium). Engineering strategies will be applied to human NK cell therapeutic platforms (Norway) towards generating cellular products for clinical trials.
This research will determine the metabolic restraints experienced by GBM infiltrating NK cells that impair cytotoxicity and develop new strategies to bolster therapeutic NK cells to open a new horizon for effective NK cell-based immunotherapies for GBM.