title: The Aryl Hydrocarbon Receptor Antagonist StemRegenin1 Improves In Vitro Generation of Highly Functional Natural Killer Cells from CD34(+) Hematopoietic Stem and Progenitor Cells.
abstract: Early natural killer (NK)-cell repopulation after allogeneic stem cell transplantation (allo-SCT) has been associated with reduced relapse rates without an increased risk of graft-versus-host disease, indicating that donor NK cells have specific antileukemic activity. Therefore, adoptive transfer of donor NK cells is an attractive strategy to reduce relapse rates after allo-SCT. Since NK cells of donor origin will not be rejected, multiple NK-cell infusions could be administered in this setting. However, isolation of high numbers of functional NK cells from transplant donors is challenging. Hence, we developed a cytokine-based ex vivo culture protocol to generate high numbers of functional NK cells from granulocyte colony-stimulating factor (G-CSF)-mobilized CD34(+) hematopoietic stem and progenitor cells (HSPCs). In this study, we demonstrate that addition of aryl hydrocarbon receptor antagonist StemRegenin1 (SR1) to our culture protocol potently enhances expansion of CD34(+) HSPCs and induces expression of NK-cell-associated transcription factors promoting NK-cell differentiation. As a result, high numbers of NK cells with an active phenotype can be generated using this culture protocol. These SR1-generated NK cells exert efficient cytolytic activity and interferon-γ production toward acute myeloid leukemia and multiple myeloma cells. Importantly, we observed that NK-cell proliferation and function are not inhibited by cyclosporin A, an immunosuppressive drug often used after allo-SCT. These findings demonstrate that SR1 can be exploited to generate high numbers of functional NK cells from G-CSF-mobilized CD34(+) HSPCs, providing great promise for effective NK-cell-based immunotherapy after allo-SCT.
authors.affiliation: 1 Department of Hematology, Radboud University Medical Center , Nijmegen, the Netherlands .|2 Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center , Nijmegen, the Netherlands .
authors.forename: Mieke W H
authors.initials: MW
authors.lastname: Roeven
authors.affiliation: 2 Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center , Nijmegen, the Netherlands .
authors.forename: Soley
authors.initials: S
authors.lastname: Thordardottir
authors.affiliation: 2 Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center , Nijmegen, the Netherlands .
authors.forename: Arwa
authors.initials: A
authors.lastname: Kohela
authors.affiliation: 2 Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center , Nijmegen, the Netherlands .
authors.forename: Frans
authors.initials: F
authors.lastname: Maas
authors.affiliation: 2 Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center , Nijmegen, the Netherlands .
authors.forename: Frank
authors.initials: F
authors.lastname: Preijers
authors.affiliation: 2 Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center , Nijmegen, the Netherlands .
authors.forename: Joop H
authors.initials: JH
authors.lastname: Jansen
authors.affiliation: 1 Department of Hematology, Radboud University Medical Center , Nijmegen, the Netherlands .
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Blijlevens
authors.affiliation: 2 Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center , Nijmegen, the Netherlands .
authors.forename: Jeannette
authors.initials: J
authors.lastname: Cany
authors.affiliation: 1 Department of Hematology, Radboud University Medical Center , Nijmegen, the Netherlands .
authors.forename: Nicolaas
authors.initials: N
authors.lastname: Schaap
authors.affiliation: 2 Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center , Nijmegen, the Netherlands .
authors.forename: Harry
authors.initials: H
authors.lastname: Dolstra
mesh_terms: D018952:Antigens, CD34 / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D011687:Purines / Q000494:pharmacology*; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors*
chemical_list: D018952:Antigens, CD34; D011687:Purines; D018336:Receptors, Aryl Hydrocarbon; C552240:StemRegenin 1; D007371:Interferon-gamma; D016572:Cyclosporine