Investigating the Metabolic Mechanisms Underlying Natural Killer Cell Dysfunction

Abstract

In cancer, Natural Killer (NK) cells often lose their immune functions and fail to eliminate tumour cells in a phenomenon called NK cell dysfunction. Unfortunately, the mechanisms and drivers of NK cell dysfunction are unknown, making it hard to revert it therapeutically. As NK cell function is tightly regulated by their metabolic state, we hypothesize that dysregulated metabolism drives NK cell dysfunction. Thus, we investigated the metabolism of dysfunctional NK cells compared to functional NK cells using an in vitro model of chronic stimulation. Dysfunctional NK cells had decreased glycolysis and transcription of glucose transporters. An untargeted metabolomics screen revealed that the pentose phosphate pathway, nucleotide metabolism, arginine metabolism and glutathione synthesis were disrupted in dysfunctional NK cells. Preliminary data shows that glutathione supplementation increased function and glycolysis in dysfunctional NK cells. This project aims to identify metabolic drivers of NK cell dysfunction to reveal new targets for cancer immunotherapies.