title: Cytokine-Induced Memory-Like Differentiation Enhances Unlicensed Natural Killer Cell Antileukemia and FcγRIIIa-Triggered Responses.
abstract: Cytokine-induced memory-like natural killer (NK) cells differentiate after short-term preactivation with IL-12, IL-15, and IL-18 and display enhanced effector function in response to cytokines or tumor targets for weeks after the initial preactivation. Conventional NK cell function depends on a licensing signal, classically delivered by an inhibitory receptor engaging its cognate MHC class I ligand. How licensing status integrates with cytokine-induced memory-like NK cell responses is unknown. We investigated this interaction using killer cell immunoglobulin-like receptor- and HLA-genotyped primary human NK cells. Memory-like differentiation resulted in enhanced IFN-γ production triggered by leukemia targets or FcγRIIIa ligation within licensed NK cells, which exhibited the highest functionality of the NK cell subsets interrogated. IFN-γ production by unlicensed memory-like NK cells was also enhanced to a level comparable with that of licensed control NK cells. Mechanistically, differences in responses to FcγRIIIa-based triggering were not explained by alterations in key signaling intermediates, indicating that the underlying biology of memory-like NK cells is distinct from that of adaptive NK cells in human cytomegalovirus-positive individuals. Additionally, memory-like NK cells responded robustly to cytokine receptor restimulation with no impact of licensing status. These results demonstrate that both licensed and unlicensed memory-like NK cell populations have enhanced functionality, which may be translated to improve leukemia immunotherapy.
authors.affiliation: Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Julia A
authors.initials: JA
authors.lastname: Wagner
authors.affiliation: Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Berrien-Elliott
authors.affiliation: Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Maximillian
authors.initials: M
authors.lastname: Rosario
authors.affiliation: Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Leong
authors.affiliation: Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Brea A
authors.initials: BA
authors.lastname: Jewell
authors.affiliation: Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Timothy
authors.initials: T
authors.lastname: Schappe
authors.affiliation: Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Sara
authors.initials: S
authors.lastname: Abdel-Latif
authors.affiliation: Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri. Electronic address: tfehnige@wustl.edu.
authors.forename: Todd A
authors.initials: TA
authors.lastname: Fehniger
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D016207:Cytokines / Q000494:pharmacology*; D006680:HLA Antigens; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects*; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology*; D007938:Leukemia / Q000628:therapy; D008213:Lymphocyte Activation; D017452:Receptors, IgG / Q000276:immunology*; D054340:Receptors, KIR / Q000276:immunology*
chemical_list: D016207:Cytokines; C496124:FCGR3A protein, human; D006680:HLA Antigens; D017452:Receptors, IgG; D054340:Receptors, KIR; D007371:Interferon-gamma
keywords: Adoptive immunotherapy; Cytokines; NK cell; NK cell education; NK cell memory