title: Cord blood natural killer cells exhibit impaired lytic immunological synapse formation that is reversed with IL-2 exvivo expansion.
abstract: Peripheral blood natural killer (NK) cell therapy for acute myeloid leukemia has shown promise in clinical trials after allogeneic stem cell transplantation. Cord blood (CB) is another potentially rich source of NK cells for adoptive immune therapy after stem cell transplantation. Tightly regulated receptor signaling between NK cells and susceptible tumor cells is essential for NK cell-mediated cytotoxicity. However, despite expressing normal surface activating and inhibitory NK receptors, CB-derived NK cells have poor cytolytic activity. In this study, we investigate the cellular mechanism and demonstrate that unmanipulated CB-NK cells exhibit an impaired ability to form F-actin immunologic synapses with target leukemia cells compared with peripheral blood-derived NK cells. In addition, there was reduced recruitment of the activating receptor CD2, integrin leukocyte function-associated antigen-1, and the cytolytic molecule perforin to the CB-NK synapse site. Exvivo interleukin (IL)-2 expansion of CB-NK cells enhanced lytic synapse formation including CD2 and leukocyte function-associated antigen-1 polarization and activity. Furthermore, the acquired antileukemic function of IL-2-expanded CB-NK cells was validated using a nonobese diabetic severe combined immunodeficient IL-2 receptor common γ-chain null mouse model. We believe our results provide important mechanistic insights for the potential use of IL-2-expanded CB-derived NK cells for adoptive immune therapy in leukemia.
authors.affiliation: Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, Baylor College of Medicine, Houston, USA.
authors.forename: Dongxia
authors.initials: D
authors.lastname: Xing
authors.forename: Alan G
authors.initials: AG
authors.lastname: Ramsay
authors.forename: John G
authors.initials: JG
authors.lastname: Gribben
authors.forename: William K
authors.initials: WK
authors.lastname: Decker
authors.forename: Jared K
authors.initials: JK
authors.lastname: Burks
authors.forename: Mark
authors.initials: M
authors.lastname: Munsell
authors.forename: Sufang
authors.initials: S
authors.lastname: Li
authors.forename: Simon N
authors.initials: SN
authors.lastname: Robinson
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.forename: David
authors.initials: D
authors.lastname: Steiner
authors.forename: Nina
authors.initials: N
authors.lastname: Shah
authors.forename: John D
authors.initials: JD
authors.lastname: McMannis
authors.forename: Richard E
authors.initials: RE
authors.lastname: Champlin
authors.forename: Chitra
authors.initials: C
authors.lastname: Hosing
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Zweidler-McKay
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Shpall
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Bollard
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D018801:CD2 Antigens / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000235:genetics; D005312:Fetal Blood / Q000166:cytology; D006801:Humans; D054992:Immunological Synapses / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D016219:Immunotherapy, Adoptive; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics*; D007376:Interleukin-2 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000276:immunology* / Q000628:therapy*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D054353:Perforin / Q000378:metabolism; D011940:Receptor Aggregation / Q000187:drug effects / Q000235:genetics / Q000276:immunology
chemical_list: D000199:Actins; D018801:CD2 Antigens; D053631:Interleukin Receptor Common gamma Subunit; D007376:Interleukin-2; D016169:Lymphocyte Function-Associated Antigen-1; D054353:Perforin