What Defines NK Cell Functional Fate: Phenotype or Metabolism?

Abstract

NK cells are capable of an array of functions that range widely from their classic anti-tumor and anti-viral cytotoxic effector functions, to their critical regulatory roles in controlling inflammatory immune responses and promoting tissue growth. However, the mechanisms that polarize NK cells to these distinct and opposing functions are incompletely understood. NK cell functional subsets are primarily identified and studied based on phenotype, which has served as an accessible means for profiling NK cells and does offer information on NK cell activation state. However, inconsistencies have emerged in using classic phenotypes to inform function, which raise the questions: Can phenotype in fact define NK cell functional fate? What factors do profile and drive NK cell fate? In other immune cells, cell metabolism has been shown to critically determine subset polarization. There is a growing body of evidence that cell metabolism is integral to NK cell effector functions. Glucose-driven glycolysis and oxidative metabolism have been shown to drive classic NK cell anti-tumor and anti-viral effector functions. Recent studies have uncovered a critical role for metabolism in NK cell development, education, and memory generation. In this review, we will draw on the evidence to date to investigate the relationship between NK cell phenotype, metabolism, and functional fate. We explore a paradigm in which the differential activity of metabolic pathways within NK cells produce distinct metabolic fingerprints that comprehensively distinguish and drive the range of NK cell functional abilities. We will discuss future areas of study that are needed to develop and test this paradigm and suggest strategies to efficiently profile NK cells based on metabolism. Given the emerging role of metabolism in driving NK cell fates, profiling and modulating NK cell metabolism holds profound therapeutic potential to tune inflammatory and regulatory NK cell responses to treat disease.

Innate Cytokine Induced Early Release of IFNγ and CC Chemokines from Hypoxic Human NK Cells Is Independent of Glucose

“…Our result that the early release of IFNγ and CCL3/4/5 from short-term IL-15 primed and IL-12/IL-18 stimulated human NK cells is unaffected by simultaneous glucose deficiency and hypoxia supports the concept of metabolic autonomy during regulatory NK cell polarization [65], specifically, during the early innate immune response (Supplemental Discussion). We propose that cytokine induced switching to glycolysis and OxPhos to support cytotoxic activity [43,44] succeeds in a time-dependent manner.…”

Considerations of Antibody Geometric Constraints on NK Cell Antibody Dependent Cellular Cytotoxicity

“…Metabolic studies have also revealed a new aspect of NK cell biology and differentiation based on the influence of metabolic factors outside of traditional routes of cellular influence, and these studies have been well-reviewed recently ( 279 – 282 ). Indeed, large differences in metabolic processes have been identified within NK cell subsets.…”

Targeting NK Cell Checkpoint Receptors or Molecules for Cancer Immunotherapy

“…Specific stimulation or induction of the anti-tumor capacity of certain NK cell subpopulations, such as memory-like or adaptive NK cells, might achieve more powerful efficacy and better clinical outcomes. Recently, increasing evidence has highlighted the crucial role of the cellular metabolic program in directing the development, survival, proliferation, and function of immune cells, and tumors and metabolic products in the TME induce the dysfunction and exhaustion of T and NK cells by modulating cell metabolism (40,(151)(152)(153)(154). Novel strategies might emerge from increased knowledge of the metabolic requirements of activated NK cells through targeting metabolic reprogramming and related pathways or factors to improve NK cell function more effectively within the TME (155).…”