title: Activating signals dominate inhibitory signals in CD137L/IL-15 activated natural killer cells.
abstract: Natural killer (NK) cells can mediate potent antitumor effects, but factors regulating the efficiency of tumor lysis remain unclear. Studies in allogeneic stem cell transplantation highlight an important role for killer cell immunoglobulin-like receptor (KIR) mismatch in overcoming human leukocyte antigen-mediated inhibitory signals. However, other activating and inhibitory signals also modulate tumor lysis by NK cells. We used rhIL15 and artificial antigen presenting cells expressing CD137L and IL15Rα to activate and expand peripheral blood NK cells (CD137L/IL15 NK) up to 1000-fold in 3 weeks. Compared with resting NK cells, CD137L/IL15 NK cells show modest increases in KIR expression and substantial increases in NKG2D, tumor necrosis factor-related apoptosis-inducing ligand, and natural cytotoxicity receptors (NCRs: NKp30, NKp44, NKp46). Compared with resting NK cells, CD137L/IL15 NK cells mediate enhanced cytotoxicity against allogeneic and autologous tumors and KIR signaling did not substantially inhibit cytotoxicity. Rather, tumor lysis by CD137L/IL15 activated NK cells was predominantly driven by NCR signaling as blockade of NCRs dramatically diminished the lysis of a wide array of tumor targets. Furthermore, tumor lysis by CD137L/IL15 NK cells was tightly linked to NCR expression levels that peaked on day 8 to 10 after NK activation, and cytotoxicity diminished on subsequent days as NCR expression declined. We conclude that KIR mismatch is not a prerequisite for tumor killing by CD137L/IL15 NK cells and that NCR expression provides a biomarker for predicting potency of CD137L/IL15 NK cells in studies of NK cell-based immunotherapy.
authors.affiliation: Pediatric Oncology Branch, NCI, NIH Clinical Center, Bethesda, MD, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Yongzhi
authors.initials: Y
authors.lastname: Cui
authors.forename: Nga
authors.initials: N
authors.lastname: Voong
authors.forename: Marianna
authors.initials: M
authors.lastname: Sabatino
authors.forename: Dave F
authors.initials: DF
authors.lastname: Stroncek
authors.forename: Sebastien
authors.initials: S
authors.lastname: Morisot
authors.forename: Curt I
authors.initials: CI
authors.lastname: Civin
authors.forename: Alan S
authors.initials: AS
authors.lastname: Wayne
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Levine
authors.forename: Crystal L
authors.initials: CL
authors.lastname: Mackall
mesh_terms: D053330:4-1BB Ligand / Q000276:immunology*; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003602:Cytotoxicity, Immunologic; D006801:Humans; D019409:Interleukin-15 / Q000276:immunology*; D053720:Interleukin-15 Receptor alpha Subunit / Q000276:immunology; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D054340:Receptors, KIR / Q000276:immunology; D055636:Receptors, Natural Cytotoxicity Triggering / Q000276:immunology; D011994:Recombinant Proteins / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology
chemical_list: D053330:4-1BB Ligand; D019409:Interleukin-15; D053720:Interleukin-15 Receptor alpha Subunit; D054340:Receptors, KIR; D055636:Receptors, Natural Cytotoxicity Triggering; D011994:Recombinant Proteins