Metabolic changes of Interleukin-12/15/18-stimulated human NK cells

Abstract

Natural Killer (NK) cells acquire memory-like properties following a brief stimulation with IL-12, IL-15 and IL-18. These IL-12/15/18-preactivated NK cells, also known as cytokine-induced memory-like (CIML) NK cells, have been revealed as a powerful tool in cancer immunotherapy due to their persistence in the host and their increased effector functions. Several studies have shown that NK cells modulate their metabolism in response to cytokine-stimulation and other stimuli, suggesting that there is a link between metabolism and cellular functions. In this paper, we have analyzed metabolic changes associated to IL-12/15/18-stimulation and the relevance of glycolytic pathway for NK cell effector functions. We have found CIML NK cells are able to retain a metabolic profile shifted towards glycolysis seven days after cytokine withdrawal. Furthermore, we found that treatment with 2-DG differently affects distinct NK cell effector functions and is stimuli-dependent. These findings may have implications in the design of NK cell-based cancer immunotherapies.

Cytokine-induced memory-like natural killer cells for cancer immunotherapy

“…In fact, increased glycolysis was shown to be correlated with MCMV-mediated adaptive NK cells [ 67 ], pointing to the metabolic changes in the NK cells that may play a vital role in their effector functions and recall responses [ 44 ]. A very recent study by Terrén et al showed that expression of nutrient transporters including transferrin receptor (CD71), amino acid transporter (CD98) and glucose transporters (GLUT1 and GLUT3) was increased after NK cells were exposed to CIML conditions [ 68 ]. Importantly, the CIML NK cells preserved elevated expression of amino acid transporters even in the resting phase.…”

“…The study also reported that CIML NK cells undergo metabolic switch toward glycolysis which persists even after the cytokine withdrawal. Detailed analysis of the relation between glycolysis and effector function showed that the production of IFNγ and MIP-1β was sensitive to glycolysis inhibition, whereas other effector functions including TNFα secretion, degranulation and cytotoxic activity were not very sensitive to the glycolysis inhibition [ 68 ].…”

Cytokine-induced natural killer cell training is dependent on cellular metabolism and is defective in obesity

“…Therefore, such metabolic perturbations that impact upon Srebp activiation will prevent the innate training response in NK cells and the immunological advantages it affords. Recent work by Terren and colleagues investigated the metabolic requirements of cytokine trained NK cells and demonstrate a bias towards glycolysis (although it is noted that the levels of 2DG used in this study were enough to completely shut down all glycolytic activity of the cell) 36 . These studies did not investigate the requirements for training but the metabolism used by fully trained cells, but support the importance of metabolism for NK cell activity in line with our previous works 11,12,20,23,26 .…”

Functional NK Cell Activation by Ovalbumin Immunization with a Monophosphoryl Lipid A and Poly I:C Combination Adjuvant Promoted Dendritic Cell Maturation

“…NK cells are known to develop normally in recombination activating genes 1 and 2 (Rag1/2) deficient mice where T cells and B cells are absent as reported in earlier studies [48][49][50]. Nonetheless, a later study reported that RAG-deficient NK cells exhibited a diminished survival capacity upon virus-driven proliferation, as well as defects in repairing…”