Cytolytic function and survival of natural killer cells are severely altered in myelodysplastic syndromes

Abstract

Natural Killer (NK) cells are critical in host defense against malignant transformation and are potent antileukemic cytotoxic effectors. In the present study, we investigated the peripheral NK function in patients with myelodysplastic syndromes (MDS). We demonstrated that the peripheral NK cell population was quantitatively normal in MDS patients. Furthermore, NK cells displayed an expression of the activating natural cytotoxicity receptors (NCR) NKp46 and NKp30 as well as NKG2D similar to that observed in donors, but exert a highly decreased constitutive cytolytic activity compared to resting normal NK cells. Although activation with IL-2 resulted in the upregulation of NKp46 expression by MDS-NK cells, their cytolytic function remained deeply altered as compared to activated donor NK cells. In addition, MDS NK cells did not proliferate in vitro, and displayed an increased rate of apoptosis in response to IL-2 stimulation although the spontaneous apoptosis was not significantly increased. Interestingly, a proportion of peripheral MDS-NK cells were derived from the MDS clone as the cytogenetic anomaly found in bone marrow karyotype was also detected in 20-50% of circulating NK cells. In conclusion, NK cells' cytolytic function and proliferative capacities in response to activation by cytokines are profoundly altered in MDS.

Reduced DNAM-1 expression on bone marrow NK cells associated with impaired killing of CD34+ blasts in myelodysplastic syndrome

“…Collectively, our results provide novel conducted the first comprehensive analysis of peripheral blood NK cells in patients with MDS, and described a global defect in NK-cell cytotoxicity and proliferation that was not reflected by changes in surface expression of activating receptors. 28 Moreover, the functional defects were not restricted to specific subgroups of patients but extended to both low-and high-risk MDS. The poor function of NK cells was attributed to the fact that a proportion of the NK cells carried the same genetic alteration as the CD34 þ blast cells.…”

“…Corroborating previous studies, CD56 dim NK cells from peripheral blood of MDS patients also showed reduced degranulation compared with cells from healthy donors, (Figures 3a and c). 25,28 Further, to more precisely investigate the capacity of surface receptors to elicit NK-cell degranulation, we used a previously described assay, in which NK cells were co-incubated with P815 cells preincubated with antibodies for specific NK-cell receptors. 31 These experiments revealed that degranulation induced by co-activation of either NKG2D or DNAM-1 in combination with 2B4 was reduced in CD56 dim NK cells from both bone marrow and peripheral blood of MDS patients, as compared with that of NK cells from healthy controls (Figures 3d and e).…”

“…[22][23][24][25][26] Previous studies have shown reduced peripheral blood NK-cell function in MDS patients. 25,[27][28][29] In one such study, reduced NK-cell function was described in patients with all subtypes of MDS, despite intact expression of activating NK-cell receptors. 28 In another study, dysfunction of NK cells was, at least in part, attributed to down-regulation of NKG2D and NKp30.…”

“…25,[27][28][29] In one such study, reduced NK-cell function was described in patients with all subtypes of MDS, despite intact expression of activating NK-cell receptors. 28 In another study, dysfunction of NK cells was, at least in part, attributed to down-regulation of NKG2D and NKp30. 25 In the latter study, reduced receptor expression and decreased NK-cell function was mainly observed in patients with high-risk MDS, suggesting that disease progression may be associated with evasion of NK cell-mediated immune surveillance.…”

Efficacy of lenalidomide in an sAML patient with del 5q relapsing after reduced-intensity allogeneic stem cell transplantation performed in complete remission

“…The cytolytic function and proliferative capacities of NK cells in response to activation by cytokines are profoundly altered in MDS. 7 It has been suggested that the impairment of NK cytolytic function in MDS, which accompanies disease progression, could be restored with lenalidomide. 8 Moreover, NK alloreactivity after allo-SCT has a major role in the graft-versus-leukemia effect without causing GVHD.…”