title: NKG2D ligand expression in AML increases in response to HDAC inhibitor valproic acid and contributes to allorecognition by NK-cell lines with single KIR-HLA class I specificities.
abstract: This study exploited alloreactivity of natural killer (NK) cells for augmenting the recognition of human acute myeloid leukemia (AML). To circumvent the inhibitory effect of killer immunoglobulin receptor (KIR) signaling, we generated NK-cell lines with single KIR specificities for major human leukocyte antigen (HLA) class I allotypes. We demonstrated efficient cytolysis of KIR-HLA class I-mismatched primary AML blasts even at low effector-to-target ratios. To define the impact of tumor-associated activating NKG2D-ligands (NKG2D-L), 66 AML patients at diagnosis were analyzed. NKG2D-L were selectively expressed on monoblastic cells in AML M4 and M5 yet absent or weakly expressed on myeloblastic cells in all AML subtypes. Paucity of cell-surface NKG2D-L was not the result of shedding because levels of soluble ULBP1 ligand measured in AML plasma were in the normal range. Notably, purified NKG2D-L(+) monoblastic cells were more susceptible to NK-mediated killing than NKG2D-L(-) myeloblastic cells. Accordingly, induction of cell-surface NKG2D-L by treatment with the histone deacetylase inhibitor, valproic acid, rendered cells more sensitive to NK cytolysis. These data suggest that adoptive transfer of selected populations of alloreactive HLA class I-mismatched NK cells in combination with pharmacologic induction of NKG2D-L merits clinical evaluation as novel approaches to immunotherapy of human AML.
authors.affiliation: Department of Research, University Hospital Basel, Basel, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Diermayr
authors.forename: Heike
authors.initials: H
authors.lastname: Himmelreich
authors.forename: Bojana
authors.initials: B
authors.lastname: Durovic
authors.forename: Arina
authors.initials: A
authors.lastname: Mathys-Schneeberger
authors.forename: Uwe
authors.initials: U
authors.lastname: Siegler
authors.forename: Ulrich
authors.initials: U
authors.lastname: Langenkamp
authors.forename: Jan
authors.initials: J
authors.lastname: Hofsteenge
authors.forename: Alois
authors.initials: A
authors.lastname: Gratwohl
authors.forename: André
authors.initials: A
authors.lastname: Tichelli
authors.forename: Monika
authors.initials: M
authors.lastname: Paluszewska
authors.forename: Wieslaw
authors.initials: W
authors.lastname: Wiktor-Jedrzejczak
authors.forename: Christian P
authors.initials: CP
authors.lastname: Kalberer
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Wodnar-Filipowicz
mesh_terms: D002460:Cell Line; D002470:Cell Survival; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D058851:GPI-Linked Proteins; D006680:HLA Antigens / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology*; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008024:Ligands; D008565:Membrane Proteins / Q000378:metabolism; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic / Q000378:metabolism*; D055607:Receptors, Natural Killer Cell; D012680:Sensitivity and Specificity; D012995:Solubility; D015854:Up-Regulation / Q000187:drug effects; D014635:Valproic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D058851:GPI-Linked Proteins; D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I; D056572:Histone Deacetylase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; C527085:KLRK1 protein, human; D008024:Ligands; C099187:MHC class I-related chain A; D008565:Membrane Proteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; C423231:ULBP1 protein, human; C027298:valpronic acid; D014635:Valproic Acid; D006655:Histone Deacetylases