title: Enhanced cytotoxicity of allogeneic NK cells with killer immunoglobulin-like receptor ligand incompatibility against melanoma and renal cell carcinoma cells.
abstract: Cellular inactivation through killer immunoglobulin-like receptors (KIRs) may allow neoplastic cells to evade host natural killer (NK) cell-mediated immunity. Recently, alloreactive NK cells were shown to mediate antileukemic effects against acute myelogenous leukemia (AML) after mismatched transplantation, when KIR ligand incompatibility existed in the direction of graft-versus-host disease (GVHD). Therefore, we investigated whether solid tumor cells would have similar enhanced susceptibility to allogeneic KIR-incompatible NK cells compared with their KIR-matched autologous or allogeneic counterparts. NK populations enriched and cloned from the blood of cancer patients or healthy donors homozygous for HLA-C alleles in group 1 (C-G1) or group 2 (C-G2) were tested in vitro for cytotoxicity against Epstein-Barr virus-transformed lymphoblastic cell lines (EBV-LCLs), renal cell carcinoma (RCC), and melanoma (MEL) cells with or without a matching KIR-inhibitory HLA-C ligand. Allogeneic NK cells were more cytotoxic to tumor targets mismatched for KIR ligands than their KIR ligand-matched counterparts. Bulk NK populations (CD3(-)/CD2(+)/CD56(+)) expanded 10(4)-fold from patients homozygous for C-G1 or C-G2 had enhanced cytotoxicity against KIR ligand-mismatched tumor cells but only minimal cytotoxicity against KIR ligand-matched targets. Further, NK cell lines from C-G1 or C-G2 homozygous cancer patients or healthy donors expanded but failed to kill autologous or KIR-matched MEL and RCC cells yet had significant cytotoxicity (more than 50% lysis at 20:1 effector-target [E/T] ratio) against allogeneic KIR-mismatched tumor lines. These data suggest immunotherapeutic strategies that use KIR-incompatible allogeneic NK cells might have superior antineoplastic effects against solid tumors compared with approaches using autologous NK cells.
authors.affiliation: Hematology Branch, Flow Cytometry Core Facility, National Heart, Lund, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1652, USA.
authors.forename: Takehito
authors.initials: T
authors.lastname: Igarashi
authors.forename: Jason
authors.initials: J
authors.lastname: Wynberg
authors.forename: Ramprasad
authors.initials: R
authors.lastname: Srinivasan
authors.forename: Brian
authors.initials: B
authors.lastname: Becknell
authors.forename: J Phillip
authors.initials: JP
authors.lastname: McCoy
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Dante A
authors.initials: DA
authors.lastname: Suffredini
authors.forename: W Marston
authors.initials: WM
authors.lastname: Linehan
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.forename: Richard W
authors.initials: RW
authors.lastname: Childs
mesh_terms: D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology; D002292:Carcinoma, Renal Cell / Q000276:immunology*; D045744:Cell Line, Tumor; D002999:Clone Cells; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005720:Gamma Rays / Q000009:adverse effects; D004854:Herpesvirus 4, Human / Q000276:immunology; D006648:Histocompatibility / Q000235:genetics / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology; D006650:Histocompatibility Testing; D006720:Homozygote; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007680:Kidney Neoplasms / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000528:radiation effects / Q000637:transplantation; D008024:Ligands; D008545:Melanoma / Q000276:immunology*; D011971:Receptors, Immunologic / Q000276:immunology*; D054340:Receptors, KIR
chemical_list: D015703:Antigens, CD; D015395:Histocompatibility Antigens Class I; D008024:Ligands; D011971:Receptors, Immunologic; D054340:Receptors, KIR