Dataset Information

NKG2A Down-Regulation by Dasatinib Enhances Natural Killer Cytotoxicity and Accelerates Effective Treatment Responses in Patients With Chronic Myeloid Leukemia.

ABSTRACT: Chronic myeloid leukemia (CML) is a hematological malignancy characterized by the presence of t(9;22) chromosomal translocation that results in BCR-ABL fusion gene. ABL tyrosine kinase inhibitors (TKIs), such as imatinib, nilotinib, and dasatinib, are currently the front-line treatment options for CML. Recently, natural killer (NK) cell activation and expansion have been shown to be associated with optimal treatment responses for CML. To investigate the effects and mechanisms of these TKIs on NK cells, here we characterized activating and inhibitory NK receptors in CD3-CD16+CD56dim NK cells isolated from CML patients in chronic phase (CP). The expressions of activating NK receptors, such as NKG2D, natural cytotoxicity receptor (NCR) and DNAM-1, rebounded after successful TKI treatments for CML. In contrast, among the three surveyed inhibitory receptors (NKG2A, KIR2DL1, and KIR3DL1), only the expression of NKG2A was reverted and suppressed to a very low level by dasatinib, and not by imatinib or nilotinib. CML patients treated with dasatinib indeed expressed fewer NKG2A+ NK cells, which send negative signals for induction of NK cytotoxicity. For these dasatinib-treated patients, the duration to reach major molecular response (MMR) was shorter, and significantly correlated with individual's NKG2A+ NK cell number. This clinical relevance to NKG2A was not observed in treatments with imatinib or nilotinib. In line with dasatinib-specific down-regulation of NKG2A, NK cytotoxicity evaluated by the killing assay was also significantly higher in patients treated with dasatinib than in those treated with imatinib or nilotinib. The lower NK cytotoxicity from imatinib or nilotinib treatments could be reverted by NKG2A blockade using anti-NKG2A antibody. Further in vitro experiments revealed mechanistically that dasatinib could inactivate p38 mitogen-activated protein kinase (MAPK), and consequently affect nuclear import of GATA-3 and GATA-3 transcriptional activities for NKG2A. Our results highlight the dual effects of dasatinib in direct inhibition of ABL kinase and in immunomodulation through NKG2A down-regulation, contributing to accelerated molecular responses (MR) in CML.

SUBMITTER: Chang MC

PROVIDER: S-EPMC6344416 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

NKG2A Down-Regulation by Dasatinib Enhances Natural Killer Cytotoxicity and Accelerates Effective Treatment Responses in Patients With Chronic Myeloid Leukemia.

Chang Ming-Chin MC Cheng Hung-I HI Hsu Kate K Hsu Yen-Ning YN Kao Chen-Wei CW Chang Yi-Fang YF Lim Ken-Hong KH Chen Caleb Gonshen CG

Frontiers in immunology 20190117

Chronic myeloid leukemia (CML) is a hematological malignancy characterized by the presence of <i>t</i>(9;22) chromosomal translocation that results in <i>BCR-ABL</i> fusion gene. ABL tyrosine kinase inhibitors (TKIs), such as imatinib, nilotinib, and dasatinib, are currently the front-line treatment options for CML. Recently, natural killer (NK) cell activation and expansion have been shown to be associated with optimal treatment responses for CML. To investigate the effects and mechanisms of th ...[more]

PMID: 30705677

Similar Datasets

Project description: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.

Dataset Information

NKG2A Down-Regulation by Dasatinib Enhances Natural Killer Cytotoxicity and Accelerates Effective Treatment Responses in Patients With Chronic Myeloid Leukemia.

Publications

NKG2A Down-Regulation by Dasatinib Enhances Natural Killer Cytotoxicity and Accelerates Effective Treatment Responses in Patients With Chronic Myeloid Leukemia.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets