title: A chimeric receptor with NKG2D specificity enhances natural killer cell activation and killing of tumor cells.
abstract: Natural killer (NK) cells rely on surface receptors to distinguish healthy cells from cancer cells. We designed a receptor termed NKG2D-DAP10-CD3ζ that is composed of the NK cell activating molecule NKG2D plus 2 key signaling molecules, DAP10 and CD3ζ, and evaluated its capacity to promote cancer cell killing. Retroviral transduction of NKG2D-DAP10-CD3ζ markedly increased NKG2D surface expression in NK cells, which became consistently more cytotoxic than mock-transduced cells against leukemia and solid tumor cell lines. In contrast, there was no increase in cytotoxicity against nontransformed blood and mesenchymal cells. NKG2D blockade abrogated gains in cytotoxicity to cancer cells. Receptor stimulation triggered signal transduction, secretion of IFN-γ, GM-CSF, IL-13, MIP-1α, MIP-1β, CCL5, and TNF-α, and massive release of cytotoxic granules, which persisted after 48 hours of continuous stimulation. NKG2D-DAP10-CD3ζ-expressing NK cells had considerable antitumor activity in a mouse model of osteosarcoma, whereas activated NK cells were ineffective. Thus, the cytotoxic potential of NK cells against a wide spectrum of tumor subtypes could be markedly enhanced by expression of NKG2D-DAP10-CD3ζ receptors. The development of an electroporation method that permits rapid expression of the receptor in a large number of human NK cells facilitates clinical translation of this NK-based strategy for a generalized cellular therapy that may be useful to treat a wide range of cancers.
authors.affiliation: Department of Pediatrics, National University of Singapore, Singapore.
authors.forename: Yu-Hsiang
authors.initials: YH
authors.lastname: Chang
authors.forename: John
authors.initials: J
authors.lastname: Connolly
authors.forename: Noriko
authors.initials: N
authors.lastname: Shimasaki
authors.forename: Kousaku
authors.initials: K
authors.lastname: Mimura
authors.forename: Koji
authors.initials: K
authors.lastname: Kono
authors.forename: Dario
authors.initials: D
authors.lastname: Campana
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism*
chemical_list: D055655:NK Cell Lectin-Like Receptor Subfamily K