Journal
CYTOTHERAPY
Volume 16, Issue 10, Pages 1431-1440Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.jcyt.2014.03.008
Keywords
leukemia; lymphoma; natural killer cells; NKG2D; romidepsin
Categories
Funding
- Children Cancer Research Foundation
- Pediatric Cancer Research Foundation
- Paul Luisi Foundation
- Marisa Fund
- Pediatric Academic Society
- Ashley G Foundation
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Background aims. There is a critical need to prevent and/or treat hematological relapse after allogeneic hematopoietic stem cell transplantation. The activating NKG2D receptor expressed on natural killer (NK) cells, when engaged by its corresponding ligands (MIC A/B), activates NEC cells to become cytotoxic against malignant cells. Methods. 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 NKG2D 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. Results. 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 < 0.001), REH (P < 0.001), Ramos (P < 0.001) and Jurkat cells (P < 0.001), respectively. We further demonstrated a significant increase in NEC cell mediated in vitro cytotoxicity against RS 4:11 (P < 0.004), Ramos (P < 0.05), Jurkat (P < 0.001) and REH cells (P < 0.01), respectively. Romidepsin-mediated NEC cytotoxicity was blocked by pre-incubating NEC cells with anti-NKG2D-Fc in RS 4:11 (P < 0.03) and Ramos cells (P < 0.01), respectively. Finally, non-obese diabetic/severe combined immunodeficiency mice xenografted with RS 4:11 cells had a significant increase in survival (P < 0.02) in mice treated with romidepsin and interleukin-2 activated NEC cells compared with each of these other treatment groups. Conclusions. Romidepsin significantly enhanced in vitro and in vivo NEC 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 NEC cells should be considered in patients with relapsed/refractory leukemia or lymphoma.
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