Investigating the metabolic reprogramming of cytokine-induced memory-like Natural Killer cells

Abstract

Natural Killer (NK) cells play a crucial role in early immune defense by recognising and eliminating virally infected and malignant cells. Human NK cells are highly heterogeneous and, under cytokine stimulation, can acquire long-lasting functional adaptations known as cytokine-induced memory-like (CIML) properties. CIML NK cells fall under the bracket of �trained immunity�, meaning they can exhibit non-specific, memory-like properties, initiated and sustained by epigenetic modifications and metabolic reprogramming. CIML NK cells display enhanced cytotoxicity against cancer cells compared to conventional NK cells, yet the metabolic mechanisms that sustain this phenotype and underpin CIML NK cell enhanced function remain ill-defined. This thesis presents one of the first integrated proteomic and metabolomic interrogations of CIML NK cell immunometabolism, using quantitative proteomics, targeted nutrient tracing, and flow cytometry to reveal insights into CIML NK cell metabolic reprogramming. The data presented herein demonstrates that CIML NK cells adopt a sustained proliferative and anabolic phenotype characterised by enhanced glycolysis, pentose phosphate pathway (PPP), purine metabolism, redox management, and accumulate mitochondrial mass poised for rapid mobilisation upon restimulation. This thesis also highlights the existence of functional and metabolic heterogeneity in recently identified CIML NK cell subsets. Collectively, this work establishes a more comprehensive understanding of CIML NK cell metabolism by revealing a coordinated metabolic network that underpins their function. Not only does this advance our understanding of NK cell metabolism and its role in trained immunity, but it also highlights specific metabolic pathways that could be targeted to enhance NK cell-based immunotherapies to treat malignancy and/or viral infection.