NYMC Faculty Publications

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

Author Type(s)

Faculty

DOI

10.1016/j.jcyt.2014.03.008

Journal Title

Cytotherapy

First Page

1431

Last Page

1440

Document Type

Article

Publication Date

10-1-2014

Department

Pediatrics

Keywords

Animals, Cytotoxicity, Immunologic, Depsipeptides, Gene Expression Regulation, Neoplastic, Histocompatibility Antigens Class I, Humans, Jurkat Cells, Killer Cells, Natural, Ligands, Lymphoma, Non-Hodgkin, Male, Mice, Mice, Inbred NOD, Mice, SCID, Mice, Transgenic, NK Cell Lectin-Like Receptor Subfamily K, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Transcriptional Activation, Tumor Cells, Cultured, Up-Regulation

Disciplines

Medicine and Health Sciences

Abstract

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 NK 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 NK 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 NK cytotoxicity was blocked by pre-incubating NK 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 NK cells compared with each of these other treatment groups.

CONCLUSIONS: 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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