Upregulation of NKG2D ligands in acute lymphoblastic leukemia and non-Hodgkin lymphoma cells by romidepsin and enhanced in vitro and in vivo natural killer cell cytotoxicity.

[severe combined immunodeficiency]

There is a critical need to prevent and /or treat hematological relapse after allogeneic hematopoietic stem cell transplantation . The activating NKG 2 D receptor expressed on natural killer (NK ) cells , when engaged by its corresponding ligands (MIC A /B ), activates NK cells to become cytotoxic against malignant cells .We incubated acute lymphoblastic leukemia and non-Hodgkin lymphoma cells for 24 h with 10 ng /mL of romidepsin . Flow cytometry was performed to demonstrate changes in surface expression of NKG 2 D ligands MIC A /B . In vitro and in vivo cytotoxicity was measured by means of modified Europium assay , and non-obese diabetic /severe combined immunodeficiency mice were xenografted with RS 4 :11 cells .We demonstrated an approximately 50 , 200 , 1300 and 180 -fold increase in the number of cells positive for the surface expression of MIC A /B in RS 4 :11 (P Â < 0 .001 ), REH (P Â < 0 .001 ), Ramos (P Â <Â 0 .001 ) and Jurkat cells (P Â < 0 .001 ), respectively . We further demonstrated a significant increase in NK cell-mediated in vitro cytotoxicity against RS 4 :11 (P Â < 0 .004 ), Ramos (P Â < 0 .05 ), Jurkat (P Â < 0 .001 ) and REH cells (P Â < 0 .01 ), respectively . Romidepsin-mediated NK cytotoxicity was blocked by pre-incubating NK cells with anti-NKG 2 D -Fc in RS 4 :11 (P Â < 0 .03 ) and Ramos cells (P Â < 0 .01 ), respectively . Finally , non-obese diabetic /severe combined immunodeficiency mice xenografted with RS 4 :11 cells had a significant increase in survival (P Â < 0 .02 ) in mice treated with romidepsin and interleukin-2 -activated NK cells compared with each of these other treatment groups .Romidepsin significantly enhanced in vitro and in vivo NK cell cytotoxicity mediated in part by increased MIC A /B expression on malignant cells . This translational approach of the use of romidepsin and interleukin-2 -activated NK cells should be considered in patients with relapsed /refractory leukemia or lymphoma .

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severe combined immunodeficiency

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