title: Immune evasion mediated by tumor-derived lactate dehydrogenase induction of NKG2D ligands on myeloid cells in glioblastoma patients.
abstract: Myeloid cells are key regulators of the tumor microenvironment, governing local immune responses. Here we report that tumor-infiltrating myeloid cells and circulating monocytes in patients with glioblastoma multiforme (GBM) express ligands for activating the Natural killer group 2, member D (NKG2D) receptor, which cause down-regulation of NKG2D on natural killer (NK) cells. Tumor-infiltrating NK cells isolated from GBM patients fail to lyse NKG2D ligand-expressing tumor cells. We demonstrate that lactate dehydrogenase (LDH) isoform 5 secreted by glioblastoma cells induces NKG2D ligands on monocytes isolated from healthy individuals. Furthermore, sera from GBM patients contain elevated amounts of LDH, which correlate with expression of NKG2D ligands on their autologous circulating monocytes. NKG2D ligands also are present on circulating monocytes isolated from patients with breast, prostate, and hepatitis C virus-induced hepatocellular carcinomas. Together, these findings reveal a previously unidentified immune evasion strategy whereby tumors produce soluble factors that induce NKG2D ligands on myeloid cells, subverting antitumor immune responses.
authors.affiliation: Departments of Neurological Surgery.
authors.forename: Courtney A
authors.initials: CA
authors.lastname: Crane
authors.affiliation: Pathology.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Austgen
authors.affiliation: Seattle Children's Research Institute, Seattle, WA 98101;
authors.forename: Kristen
authors.initials: K
authors.lastname: Haberthur
authors.affiliation: Departments of Neurological Surgery.
authors.forename: Carly
authors.initials: C
authors.lastname: Hofmann
authors.affiliation: Seattle Children's Research Institute, Seattle, WA 98101;
authors.forename: Kara White
authors.initials: KW
authors.lastname: Moyes
authors.affiliation: Kalmanovitz Liver Immunology Laboratory, California Pacific Medical Center and Research Institute, San Francisco, CA 94115; and.
authors.forename: Lia
authors.initials: L
authors.lastname: Avanesyan
authors.affiliation: Medicine.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Fong
authors.affiliation: Surgery, and.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Campbell
authors.affiliation: Kalmanovitz Liver Immunology Laboratory, California Pacific Medical Center and Research Institute, San Francisco, CA 94115; and Division of Hepatology, California Pacific Medical Center and Sutter Pacific Medical Foundation, San Francisco, CA 94115.
authors.forename: Stewart
authors.initials: S
authors.lastname: Cooper
authors.affiliation: Pathology.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Oakes
authors.affiliation: Departments of Neurological Surgery.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Parsa
authors.affiliation: Microbiology, University of California, San Francisco, CA 94143; lewis.lanier@ucsf.edu.
authors.forename: Lewis L
authors.initials: LL
authors.lastname: Lanier
mesh_terms: D001932:Brain Neoplasms / Q000276:immunology*; D045744:Cell Line, Tumor; D058851:GPI-Linked Proteins / Q000276:immunology; D005909:Glioblastoma / Q000276:immunology*; D005910:Glioma / Q000276:immunology; D057809:HEK293 Cells; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D057131:Immune Evasion / Q000276:immunology*; D007113:Immunity, Innate / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology; D007527:Isoenzymes / Q000276:immunology; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology; D007770:L-Lactate Dehydrogenase / Q000276:immunology*; D000080864:Lactate Dehydrogenase 5; D009000:Monocytes / Q000166:cytology / Q000276:immunology; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology*
chemical_list: D058851:GPI-Linked Proteins; D015395:Histocompatibility Antigens Class I; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; C527085:KLRK1 protein, human; C099187:MHC class I-related chain A; D055655:NK Cell Lectin-Like Receptor Subfamily K; C423231:ULBP1 protein, human; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5
keywords: LDH5; cancer; glioma; tumor evasion