Up-regulation of natural killer (NK) cell activating receptors and increase in NK mediated cytotoxicity using interleukin-15 in patients with newly diagnosed acute myeloid leukemia (AML)

Abstract

3076 Background: NK cell cytotoxicity is tightly controlled through a balance of signals from the functionally opposing activating and inhibitory receptors found on each cell. Interleukin-15 (IL-15) has a major role in NK cell homeostasis. IL-15 induces the differentiation of NK cells from hematopoietic progenitors, stimulates the expansion of peripheral NK cells and supports their survival. Modulation of the relative frequency and intensity of expression of the NK cell receptors by IL-15 may increase NK mediated cytotoxicity in cancer patients. Methods: We investigated the receptor repertoire and measured NK cell activity in the peripheral blood of 21 patients with newly diagnosed AML prior to any treatment and 15 normal donors. Ex-vivo effects of IL-15 on the NK cell repertoire and NK cell cytotoxicity were investigated. Results: The expression of the activating natural cytotoxicity (NCR) receptors NKp30 and NKp46 and the C-type lectin receptors NKG2D and NKG2C were significantly decreased in the AML patients compared to the NK cells of healthy donors (p<0.0001–0.03). Furthermore, NK cytotoxicity was significantly lower (p<0.0003) in the AML patients at diagnosis compared to that of healthy donors. When NK cells obtained from AML patients were cultured with IL-15, expression of the activating receptors was significantly increased compared to pre-culture levels: NKp30, 84 vs 20% p<0.001; NKp44, 71 vs 4% p<0.0001; NKp46, 83 vs 32% p<0.0002; NKG2D 87 vs 43% p<0.01; NKG2C, 58 vs 18% p<0.005. Concomitantly, cytotoxic activity of NK cells sorted from AML patients increased following IL-15 stimulation (790 vs 2211 LU, p<0.05). This IL-15 induced increase in the activity was blocked by neutralizing antibodies against the NK cell activating receptors. Conclusions: We determined that IL-15, a homeostatic NK cell cytokine, can upregulate the expression of the NK activating receptors and concomitantly increase the NK lytic activity in patients with AML. These data support the use of IL-15 as a platform for NK- based therapies for AML patients. No significant financial relationships to disclose.