Metabolically optimised NK cell therapies for Glioblastoma

Glioblastoma Multiforme represents one of the most intractable forms of brain cancer, posing considerable challenges to the medical community. However, recent advancements in cellular immunotherapy offer a promising avenue for treatment. Specifically, Natural Killer (NK) cells, a type of lymphocyte with the capacity to eliminate tumor cells, could play a pivotal role. Unfortunately, the microenvironment within glioblastoma tumors hinders the functionality of these NK cells. This is largely due to an array of metabolites, including fatty acids, and specific proteins that inhibit the NK cells' metabolic and cytotoxic activities. To address these challenges, a multi-faceted research approach has been designed. Initially, the focus will be on characterizing the suppressive metabolic environment that exists within these tumors. Advanced imaging technologies, such as mass spectrometry and multiplex immunofluorescence imaging, will be employed to dissect the spatial distribution of these inhibitory factors. Subsequently, this knowledge will inform the development of novel strategies aimed at enhancing the metabolic resilience and cytotoxic potential of NK cells. Methods will involve the use of flow cytometry and various microscopy techniques to determine the metabolic phenotype of NK cells that have infiltrated glioblastoma tumors. Curative strategies could include genetic engineering of NK cells and targeted antibody therapies. If successful, the outcomes of this research will pave the way for more effective NK cell-based immunotherapies for glioblastoma, offering a transformative approach to cancer treatment.

Background: Glioblastoma Multiforme (GBM) is an incurable form of brain cancer. However, there is now an opportunity to apply the advances in cellular immunotherapy to treat GBM. Natural Killer (NK) cells are cytotoxic lymphocytes that kill tumour cells. However, GBM tumours create an environment rich in metabolites (eg. fatty acids) and proteins (eg. TGF?) that potently suppress NK cell metabolism and cytotoxicity. Hypothesis: The metabolic microenvironment of GBM is a key driver of NK cell dysfunction and a limiting factor for NK cell immunotherapies. Aims: Our primary aim is to establish the nature the suppressive metabolic tumour microenvironment (TME) and to understand how this interferes with infiltrating NK cells. This will guide our secondary aim of developing novel approaches to bolster NK cell metabolism for enhanced cytotoxic activities against GBM tumours. Methods: Spatial distribution of the metabo-lipidome and TGF? actions within GBM tumours will be performed by DESI-/MALDI-mass spec imaging (Germany) and multiplex immunofluorescence imaging (Belgium). Modelling will estimate the relationship between metabolites, lipids, TGF? 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 define the metabolic phenotype of GBM infiltrating NK cells. Identified strategies such as genetic engineering of NK cells and/or antibody blockade of TGF? axis for metabolic resilience will be tested in a murine GBM model and applied to human NK cell therapeutic platforms (Norway) towards generating cellular products for clinical trials.