title: Identification of a Natural Killer Cell Receptor Allele That Prolongs Survival of Cytomegalovirus-Positive Glioblastoma Patients.
abstract: By affecting immunological presentation, the presence of cytomegalovirus in some glioblastomas may impact progression. In this study, we examined a hypothesized role for natural killer (NK) cells in impacting disease progression in this setting. We characterized 108 glioblastoma patients and 454 healthy controls for HLA-A,-B,-C, NK-cell KIR receptors, and CMV-specific antibodies and correlated these metrics with clinical parameters. Exome sequences from a large validation set of glioblastoma patients and control individuals were examined from in silico databases. We demonstrated that the KIR allele KIR2DS4*00101 was independently prognostic of prolonged survival. KIR2DS4*00101 displayed 100% concordance with cognate HLA-C1 ligands in glioblastoma patients, but not controls. In the context of both HLA-C1/C2 ligands for the KIR2DS4 receptor, patient survival was further extended. Notably, all patients carrying KIR2DS4*00101 alleles were CMV seropositive, but not control individuals, and exhibited increased NK-cell subpopulations, which expressed the cytotoxicity receptors CD16, NKG2D, and CD94/NKG2C. Finally, healthy controls exhibited a reduced risk for developing glioblastoma if they carried two KIR2DS4*00101 alleles, where protection was greatest among Caucasian individuals. Our findings suggest that KIR2DS4*00101 may offer a molecular biomarker to identify intrinsically milder forms of glioblastoma. Cancer Res; 76(18); 5326-36. ©2016 AACR.
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: Mev
authors.initials: M
authors.lastname: Dominguez-Valentin
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: Andrea
authors.initials: A
authors.lastname: Gras Navarro
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: Aminur Mohummad
authors.initials: AM
authors.lastname: Rahman
authors.affiliation: Department of Cancer Genetics, Oslo University Norwegian Radium Hospital, Institute for Cancer Research, Oslo, Norway. Division of Medicine, Department of Clinical Molecular Biology (EpiGen), Akershus University Hospital, Lørenskog, Norway.
authors.forename: Surendra
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Blood Transfusion Center Pays de la Loire, Nantes, France.
authors.forename: Christèle
authors.initials: C
authors.lastname: Retière
authors.affiliation: Department of Microbiology, Haukeland University Hospital, Bergen, Norway. Department of Clinical Medicine, University of Bergen, Bergen, Norway.
authors.forename: Elling
authors.initials: E
authors.lastname: Ulvestad
authors.affiliation: Department of Cancer Genetics, Oslo University Norwegian Radium Hospital, Institute for Cancer Research, Oslo, Norway.
authors.forename: Vessela
authors.initials: V
authors.lastname: Kristensen
authors.affiliation: Department of Clinical Medicine, University of Bergen, Bergen, Norway. Department of Neurosurgery, Haukeland University Hospital, Bergen, Norway.
authors.forename: Morten
authors.initials: M
authors.lastname: Lund-Johansen
authors.affiliation: Department of Immunology, Oslo University Hospital, Oslo, Norway.
authors.forename: Benedicte Alexandra
authors.initials: BA
authors.lastname: Lie
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway. Department of Neurosurgery, Haukeland University Hospital, Bergen, Norway.
authors.forename: Per Øyvind
authors.initials: PØ
authors.lastname: Enger
authors.affiliation: Department of Microbiology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Gro
authors.initials: G
authors.lastname: Njølstad
authors.affiliation: Department of Clinical Medicine, University of Bergen, Bergen, Norway. Department of Immunology and Transfusion Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: Einar
authors.initials: E
authors.lastname: Kristoffersen
authors.affiliation: Department of Clinical Dentistry, University of Bergen, Bergen, Norway. martha.enger@uib.no Stein.Lie@uib.no.
authors.forename: Stein Atle
authors.initials: SA
authors.lastname: Lie
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway. martha.enger@uib.no Stein.Lie@uib.no.
authors.forename: Martha
authors.initials: M
authors.lastname: Chekenya
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D014408:Biomarkers, Tumor / Q000032:analysis / Q000276:immunology*; D001932:Brain Neoplasms / Q000276:immunology* / Q000401:mortality / Q000821:virology; D002648:Child; D003586:Cytomegalovirus Infections / Q000150:complications; D005260:Female; D005434:Flow Cytometry; D005909:Glioblastoma / Q000276:immunology* / Q000401:mortality / Q000821:virology; D006801:Humans; D053208:Kaplan-Meier Estimate; D007694:Killer Cells, Natural / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011379:Prognosis; D016016:Proportional Hazards Models; D054340:Receptors, KIR / Q000276:immunology*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C473953:KIR2DS4 protein, human; D054340:Receptors, KIR