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 |
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| Institution: | 1. Department of Pediatrics, Columbia University, New York, New York, USA;2. Department of Pediatrics, New York Medical College, Valhalla, New York, USA;3. Department of Medicine, New York Medical College, Valhalla, New York, USA;4. Department of Pathology, New York Medical College, Valhalla, New York, USA;5. Department of Microbiology and Immunology, New York Medical College, Valhalla, New York, USA;6. Department of Cell Biology and Anatomy, New York Medical College, Valhalla, New York, USA;1. Division of Plastic and Hand Surgery, University Hospital Zurich, Zurich, Switzerland;2. Department of Clinical Research, University of Bern, Bern, Switzerland;3. Center for Clinical Research, University of Zurich, Zurich, Switzerland;4. Department of Ophthalmology, University of Bern, Inselspital, Bern, Switzerland;1. Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Shonan Research Center, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan;2. Product Information Group Japan Oncology Business Unit, Takeda Pharmaceutical Co., Ltd., 12-10, Nihonbashi 2-Chome, Chuo-ku, Tokyo 103-8686, Japan;1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA;2. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA;3. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA;4. Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland;5. Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115, USA;6. Broad Institute, Cambridge, MA 02142, USA;1. Oncohematology Research Group, Navarrabiomed, Miguel Servet Foundation, Pamplona, Spain;2. Department of Haematology, Complejo Hospitalario de Navarra, Navarra Health Service, Pamplona, Spain;3. Department of Haematology, University College London Medical School, University College London, London, United Kingdom;1. Department of Surgery, Chonnam National University Medical School, Gwangju, Korea;2. Research Center for Cancer Immunotherapy, Chonnam National University, Hwasun Hospital, Jeollanam-do, Korea;3. Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea;4. Department of Companion & Laboratory Animal Science, Kongju National University, Yesan, Korea;5. Department of Laboratory Medicine, Chonnam National University Medical School, Gwangju, Korea;6. Center for Creative Biomedical Scientists at Chonnam National University, Gwangju, Korea;7. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada;8. Department of Radiation Oncology, Chonnam National University Medical School, Gwangju, Korea;1. Department of Orthopedics, Korea University Ansan Hospital, Ansan, South Korea;2. Next-Generation Pharmaceutical Research Center, Korea Institute of Toxicology, Daejeon, Republic of Korea;3. Scoliosis Research Institute, Department of Orthopedics, Korea University Guro Hospital, Seoul, South Korea |
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| Abstract: | Background aimsThere 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.MethodsWe 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.ResultsWe 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.ConclusionsRomidepsin 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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| Keywords: | leukemia lymphoma natural killer cells NKG2D romidepsin |
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