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.
Highlights
Natural Killer (NK) cells acquire memory-like properties following a brief stimulation with IL-12, IL-15 and IL-18
We have found that NK cells increase the expression of the transferrin receptor CD71, the heavy subunit of multiple heterodimeric amino acid transporters CD98, and the glucose transporters GLUT1 and GLUT3, following stimulation with IL-12, IL-15 and IL-18 for 16–18 h, i.e. at day 0 (Fig. 1, left column)
Our results showed that activated NK cells tended to have a lower oxygen consumption rate (OCR):extracellular acidification rate (ECAR) ratio, the difference is better observed after seven days, indicating that cytokine-induced memory-like (CIML) NK cells undergo a metabolic switch towards glycolysis that is not stopped following cytokine withdrawal (Fig. 2D)
Summary
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, known as cytokine-induced memorylike (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. Glycolytic pathway is essential in mouse NK cells for IFNγ and granzyme B production, the mechanisms that regulate each function could be d ifferent[35] Certain pathologies such as obesity and cancer lead to altered metabolic activity, which has been linked to dysfunctional NK cells[36,37,38]. We have explored the different glycolytic requirements of several effector functions of IL-12/15/18-preactivated NK cells in response to different stimuli
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