Interleukin-15 Upregulates the Expression of NK-Cell Activating Receptors and Concomitantly Increases the NK Cytotoxicity in Patients with Acute Myeloid Leukemia.

Abstract

Natural killer (NK) cells lyse malignant cells without prior antigen-specific priming and play a critical role in the innate immune response. A balance of signals from activating and inhibiting receptors expressed on each NK cell controls its activity. The growth, differentiation and survival of NK cells have been found to be dependent on interleukin-15 (IL-15). Using multicolor flow cytometry we investigated the receptor repertoire and also measured the NK cell activity in twenty three patients with newly diagnosed acute myeloid leukemia (AML) prior to any treatment. Further, we investigated the ex-vivo effect of IL-15 on the NK cell repertoire and NK cell cytotoxicity. 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%). The expression of the activating natural cytotoxicity (NCR) receptors NKp30 and NKp46 and the C-type lectin receptors NKG2D and NKG2C was significantly decreased in the AML patients compared to the NK cells of healthy donors: NKp30 24 vs 51% p<0.0001, NKp46 32 vs 73% p<0.0001, NKG2D 43 vs 83% p<0.0001, NKG2C 17 vs 28% p<0.03. In addition, the receptor expression (mean fluorescence intensity, MFI) was also significantly lower in AML patients compared to healthy donors. No significant differences in the expression of the NCR NKp44 and the NK- cell inhibitory receptors were observed. Furthermore, the NK cytotoxicity in the AML patients at diagnosis was significantly lower (p<0.0003) compared to the NK cytotoxicity of healthy donors (4 vs 75 LU). When NK cells obtained from AML patients were cultured with IL-15, significant increases in the expression of the NK- cell activating receptors (Table 1) were observed. The upregulation of the activating receptors was associated with a concomitant significant increase (p<0.001) of the NK cell cytotoxicity (4 vs 70 LU). The data suggest that IL-15, a homeostatic NK cell cytokine, can upregulate the expression of activating receptors and concomitantly increase the NK lytic activity. The use of IL-15 as a platform for NK- based therapies for AML patients should be considered in the future.Table 1The effect of IL-15 on the receptor expression in AML patientsNK cell Activating ReceptorsNK cells in AML pts at diagnosisNK cells in AML pts after IL-15 stimulationp value% positive, MFI% positive, MFINKp3024, 2.684, 6.00.001NKp444, 2.471, 6.70.001NKp4632, 2.683, 70.002NKG2C17, 2.258, 6.90.005NKG2D43, 2.587, 7.80.01