title: Human NK cells maintain licensing status and are subject to killer immunoglobulin-like receptor (KIR) and KIR-ligand inhibition following ex vivo expansion.
abstract: Infusion of allogeneic NK cells is a potential immunotherapy for both hematopoietic malignancies and solid tumors. Interactions between killer immunoglobulin-like receptors (KIR) on human NK cells and KIR-ligands on tumor cells influence the magnitude of NK function. To obtain sufficient numbers of activated NK cells for infusion, one potent method uses cells from the K562 human erythroleukemia line that have been transfected to express activating 41BB ligand (41BBL) and membrane-bound interleukin 15 (mbIL15). The functional importance of KIRs on ex vivo expanded NK cells has not been studied in detail. We found that after a 12-day co-culture with K562-mbIL15-41BBL cells, expanded NK cells maintained inhibition specificity and prior in vivo licensing status determined by KIR/KIR-ligand interactions. Addition of an anti-CD20 antibody (rituximab) induced NK-mediated antibody-dependent cellular cytotoxicity and augmented killing of CD20+ target cells. However, partial inhibition induced by KIR/KIR-ligand interactions persisted. Finally, we found that extended co-cultures of NK cells with stimulatory cells transduced to express various KIR-ligands modified both the inhibitory and activating KIR repertoires of the expanded NK cell product. These studies demonstrate that the licensing interactions known to occur during NK ontogeny also influence NK cell function following NK expansion ex vivo with HLA-null stimulatory cells.
authors.affiliation: Department of Human Oncology, University of Wisconsin, 4159 WIMR Bldg. UW-Madison Campus, 1111 Highland Avenue, Madison, WI, 53705, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Human Oncology, University of Wisconsin, 4159 WIMR Bldg. UW-Madison Campus, 1111 Highland Avenue, Madison, WI, 53705, USA.
authors.forename: Amy K
authors.initials: AK
authors.lastname: Erbe
authors.affiliation: Department of Human Oncology, University of Wisconsin, 4159 WIMR Bldg. UW-Madison Campus, 1111 Highland Avenue, Madison, WI, 53705, USA.
authors.forename: Kory A
authors.initials: KA
authors.lastname: Alderson
authors.affiliation: Department of Human Oncology, University of Wisconsin, 4159 WIMR Bldg. UW-Madison Campus, 1111 Highland Avenue, Madison, WI, 53705, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Phillips
authors.affiliation: Department of Human Oncology, University of Wisconsin, 4159 WIMR Bldg. UW-Madison Campus, 1111 Highland Avenue, Madison, WI, 53705, USA.
authors.forename: Mikayla
authors.initials: M
authors.lastname: Gallenberger
authors.affiliation: Department of Human Oncology, University of Wisconsin, 4159 WIMR Bldg. UW-Madison Campus, 1111 Highland Avenue, Madison, WI, 53705, USA.
authors.forename: Jacek
authors.initials: J
authors.lastname: Gan
authors.affiliation: Department of Pediatrics, National University of Singapore, Singapore, Singapore.
authors.forename: Dario
authors.initials: D
authors.lastname: Campana
authors.affiliation: Department of Human Oncology, University of Wisconsin, 4159 WIMR Bldg. UW-Madison Campus, 1111 Highland Avenue, Madison, WI, 53705, USA.
authors.forename: Jacquelyn A
authors.initials: JA
authors.lastname: Hank
authors.affiliation: Department of Human Oncology, University of Wisconsin, 4159 WIMR Bldg. UW-Madison Campus, 1111 Highland Avenue, Madison, WI, 53705, USA. pmsondel@humonc.wisc.edu.|Department of Pediatrics, University of Wisconsin, Madison, WI, USA. pmsondel@humonc.wisc.edu.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Sondel
mesh_terms: D000920:Antibody-Dependent Cell Cytotoxicity; D045744:Cell Line, Tumor; D060005:Genotyping Techniques; D015236:HLA-C Antigens / Q000276:immunology*; D006801:Humans; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology*; D008024:Ligands; D054340:Receptors, KIR / Q000276:immunology*; D014162:Transfection
chemical_list: D015236:HLA-C Antigens; D008024:Ligands; D054340:Receptors, KIR
keywords: ADCC; Ex vivo expansion; HLA; Killer immunoglobulin-like receptors; NK cells