Bortezomib enhances cytotoxicity of ex vivo-expanded gamma delta T cells against acute myeloid leukemia and T-cell acute lymphoblastic leukemia |
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| Authors: | Jamie Y Story Jaquelyn T Zoine Rebecca E Burnham Jamie AG Hamilton H Trent Spencer Christopher B Doering Sunil S Raikar |
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| Institution: | 1. Molecular and Systems Pharmacology Graduate Program, Graduate Division of Biological and Biomedical Sciences, Laney Graduate School, Emory University School of Medicine, Atlanta, Georgia, USA;2. Cancer Biology Graduate Program, Graduate Division of Biological and Biomedical Sciences, Laney Graduate School, Emory University School of Medicine, Atlanta, Georgia, USA;3. Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA;4. Aflac Cancer and Blood Disorders Center, Children''s Healthcare of Atlanta, Atlanta, Georgia, USA;1. Department of Chemistry and Biotechnology, Faculty of Science, Engineering and Technology, Swinburne University of Technology, Hawthorn, Australia;2. Regenerative Medicine and Stem Cell Laboratory, Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Medak, India;3. ARC Training Centre in Surface Engineering for Advanced Materials, School of Engineering, Swinburne University of Technology, Hawthorn, Australia;1. Center for Autoimmune Genomics and Etiology, Cincinnati Children''s Hospital Medical Center, Cincinnati, Ohio, USA;2. Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA;3. Immunology Graduate Training Program, Cincinnati, Ohio, USA;4. Molecular and Developmental Biology Graduate Program, Cincinnati, Ohio, USA;5. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA;6. Division of Rheumatology, Cincinnati Children''s Hospital Medical Center, Cincinnati, Ohio, USA;1. Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, Guangdong Provincial Center for Quality Control of Minimally Invasive Spine Surgery, Guangzhou, People''s Republic of China;2. Cell-Gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People''s Republic of China;1. Center for Cancer and Immunology Research, Children''s National Hospital, Washington, DC, USA;2. Division of Allergy and Immunology, Children''s National Hospital, Washington, DC, USA;3. Division of Blood and Marrow Transplantation, Children''s National Hospital, Washington, DC, USA;4. The George Washington University Cancer Center, Washington, DC, USA |
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| Abstract: | Engagement between the natural killer group 2, member D (NKG2D) receptor and its ligands is one of the main mechanisms used by immune cells to target stressed cells for cell death. NKG2D ligands are known markers of cellular stress and are often upregulated on tumor cells. Certain drugs can further increase NKG2D ligand levels, thereby making tumor cells more susceptible to immune cell detection and destruction. However, the effectiveness of this approach appears to be limited with drug treatment alone, possibly due to immune dysregulation in the setting of malignancies. We hypothesized that a more effective approach would be a combination of NKG2D ligand-inducing drugs, such as the proteasome inhibitor bortezomib, and ex vivo-expanded peripheral blood γδ T cells (i.e., Vγ9Vδ2 T cells). Acute myeloid leukemia (AML) is a high-risk hematologic malignancy, and treatment has shown limited benefit with the addition of bortezomib to standard chemotherapy regimens. Two AML cells lines, Nomo-1 and Kasumi-1, were treated with increasing concentrations of bortezomib, and changes in NKG2D ligand expression were measured. Bortezomib treatment significantly increased expression of the NKG2D ligand UL16 binding protein (ULBP) 2/5/6 in both cell lines. Vγ9Vδ2 T cells were expanded and isolated from peripheral blood of healthy donors to generate a final cellular product with a mean of 96% CD3+/γδ T-cell receptor-positive cells. Combination treatment of the AML cell lines with γδ T cells and bortezomib resulted in significantly greater cytotoxicity than γδ T cells alone, even at lower effector-to-target ratios. Based on the positive results against AML and the generalizable mechanism of this combination approach, it was also tested against T-cell acute lymphoblastic leukemia (T-ALL), another high-risk leukemia. Similarly, bortezomib increased ULBP 2/5/6 expression in T-ALL cell lines, Jurkat and MOLT-4 and improved the cytotoxicity of γδ T cells against each line. Collectively, these results show that bortezomib enhances γδ T-cell-mediated killing of both AML and T-ALL cells in part through increased NKG2D ligand-receptor interaction. Furthermore, proof-of-concept for the combination of ex vivo-expanded γδ T cells with stress ligand-inducing drugs as a therapeutic platform for high-risk leukemias is demonstrated. |
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