title: Human anaplastic thyroid carcinoma cells are sensitive to NK cell-mediated lysis via ULBP2/5/6 and chemoattract NK cells.
abstract: OBJECTIVE
  Anaplastic thyroid carcinoma (ATC) is one of the most aggressive forms of cancer with no curative therapies available. To date, strategies to target ATC by immunotherapy have not been evaluated. We investigated whether ATC would be a suitable target for natural killer (NK) cell-based immunotherapy.
  
  
  METHODS
  We first established seven new cell lines from ATC tumors, three from papillary thyroid carcinoma tumors and analyzed them together with eight additional ATC cell lines. Cells were analyzed for sensitivity to lysis by NK cells and their ability to chemoattract and regulate the activity of NK cells. In addition, fresh tumor samples and peripheral blood from six patients with ATC were analyzed for NK cell infiltration and phenotype.
  
  
  RESULTS
  We observed that ATC cell lines are sensitive to lysis by ex vivo expanded NK cells and that the lysis was abrogated upon blockade of NKG2D. Sensitivity of thyroid cancer cell lines to NK cell-mediated lysis correlated with surface expression of UL16-binding protein 2 on tumor cells. Moreover, ATC cell lines produced high levels of CXCL10 and stimulated migration of expanded NK cells and ATC tumors were enriched for NK cells expressing the cognate chemokine receptor CXCR3. However, compared with NK cells in peripheral blood, ATC tumor-derived NK cells displayed a suppressed phenotype with a downregulated expression of NKG2D. In vitro, suppression of NK cell-mediated lysis and NKG2D expression by ATC cells was restored upon neutralization of prostaglandin-E2.
  
  
  CONCLUSIONS
  ATC cell lines are sensitive to NK cell-mediated lysis via ULBP2/5/6 and chemoattract CXCR3-positive NK cells. Patients with ATC may benefit from NK cell-based immunotherapy.
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Wennerberg
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Aline
authors.initials: A
authors.lastname: Pfefferle
authors.affiliation: Division of Oncology and Pathology, Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Ekblad
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Yoshimoto
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Veronika
authors.initials: V
authors.lastname: Kremer
authors.affiliation: Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Vitaliy O
authors.initials: VO
authors.lastname: Kaminskyy
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden.
authors.forename: C Christofer
authors.initials: CC
authors.lastname: Juhlin
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Höög
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Inger
authors.initials: I
authors.lastname: Bodin
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Vitalijs
authors.initials: V
authors.lastname: Svjatoha
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Catharina
authors.initials: C
authors.lastname: Larsson
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Zedenius
authors.affiliation: Division of ORL/Head&Neck Surgery, Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Wennerberg
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden. andreas.lundqvist@ki.se.
authors.forename: Andreas
authors.initials: A
authors.lastname: Lundqvist
mesh_terms: D019138:Antibodies, Blocking / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D045744:Cell Line, Tumor; D054357:Chemokine CXCL10 / Q000096:biosynthesis; D002633:Chemotaxis / Q000276:immunology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D015232:Dinoprostone / Q000378:metabolism; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D016130:Immunophenotyping; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000037:antagonists & inhibitors / Q000378:metabolism; D010641:Phenotype; D054367:Receptors, CXCR3 / Q000235:genetics / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000037:antagonists & inhibitors / Q000378:metabolism; D065646:Thyroid Carcinoma, Anaplastic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D054357:Chemokine CXCL10; D058851:GPI-Linked Proteins; D036341:Intercellular Signaling Peptides and Proteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; D054367:Receptors, CXCR3; D053221:TNF-Related Apoptosis-Inducing Ligand; C423230:ULBP2 protein, human; D051546:Cyclooxygenase 2; D015232:Dinoprostone