The Role of Interleukin-15 on Natural Killer Cell Homeostasis and Activity in Patients with Acute Myeloid Leukemia

Abstract

Interleukin-15 (IL-15) has been demonstrated to play a critical role in the regulation of natural killer (NK) cells. IL-15 induces the differentiation of NK cells from hematopoietic progenitors, stimulates the expansion of peripheral NK cells, and supports their survival. We investigated the role of IL-15 as a homeostatic regulator of NK cells in 29 patients diagnosed with acute myeloid leukemia (AML) and the potential role of IL-15 in enhancing the anti-tumor activity of NK cells in AML patients. The percentage of circulating NK cells was lower (p<0.0001) in the AML patients (6%± 0.7, range 1–17%) compared to the NK cells of healthy donors (12%± 1, range 9–17 %). At diagnosis the mean level of IL-15 in patient plasma was 1.9 pg/ml (range 0.03–8.9) and increased (p <0.02) to 5.2 pg/ml (range 0.06–13.4) after the completion of induction chemotherapy, when the NK levels had been reduced to zero cells/microliter. The mean level of IL-15 subsequently decreased to pre-treatment levels in the AML patients who achieved complete remission (mean 1.6 pg/ml, range 0.4–2.3). To assess effects of IL-15 on the NK cytotoxicity, we sorted NK cells from PBMC obtained from AML patients prior to treatment (at diagnosis) and cultured them in the presence of IL-15. Following IL-15 stimulation, a significant increase in NK-cell cytotoxicity against K562 targets and the patients' autologous leukemic blasts was observed (p<0.05) as was up-regulation in expression of the activating natural cytotoxicity receptors, NKp30 and NKp46 and the C-type lectin receptors NKG2D and NKG2C (p<0.02–0.001). Addition of blocking antibodies to the activating receptors reduced NK-cell cytotoxicity. We determined that IL-15, a homeostatic NK-cell cytokine, increases after severe depletion of NK cells following intensive chemotherapy and this leads to increased NK-cell lytic activity in AML patients. These data suggest that modulation of IL-15 levels in AML could be therapeutically beneficial as IL-15 enhances NK-cell recovery following intensive chemotherapy and increases NK-cell anti-tumor activity.