title: Defective NK Cells in Acute Myeloid Leukemia Patients at Diagnosis Are Associated with Blast Transcriptional Signatures of Immune Evasion.
abstract: Acute myeloid leukemia (AML) is a heterogeneous group of malignancies that may be sensitive to the NK cell antitumor response. However, NK cells are frequently defective in AML. In this study, we found in an exploratory cohort (n = 46) that NK cell status at diagnosis of AML separated patients in two groups with a different clinical outcome. Patients with a deficient NK cell profile, including reduced expression of some activating NK receptors (e.g., DNAX accessory molecule-1, NKp46, and NKG2D) and decreased IFN-γ production, had a significantly higher risk of relapse (p = 0.03) independently of cytogenetic classification in multivariate analysis. Patients with defective NK cells showed a profound gene expression decrease in AML blasts for cytokine and chemokine signaling (e.g., IL15, IFNGR1, IFNGR2, and CXCR4), Ag processing (e.g., HLA-DRA, HLA-DRB1, and CD74) and adhesion molecule pathways (e.g., PVR and ICAM1). A set of 388 leukemic classifier genes defined in the exploratory cohort was independently validated in a multicentric cohort of 194 AML patients. In total, these data evidenced the interplay between NK cells and AML blasts at diagnosis allowing an immune-based stratification of AML patients independently of clinical classifications.
authors.affiliation: INSERM, Unité Mixte de Recherche-S1160, 75010 Paris, France; Institut Universitaire d'Hématologie, Université Paris Diderot, Sorbonne Paris Cité, 75010 Paris, France;
authors.forename: Zena
authors.initials: Z
authors.lastname: Khaznadar
authors.affiliation: Institut Universitaire d'Hématologie, Université Paris Diderot, Sorbonne Paris Cité, 75010 Paris, France; Service d'Hématologie Adulte, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, 75010 Paris, France; Université Paris Diderot, Sorbonne Paris Cité, EA3518, 75010 Paris, France;
authors.forename: Nicolas
authors.initials: N
authors.lastname: Boissel
authors.affiliation: INSERM, Unité Mixte de Recherche-S1160, 75010 Paris, France; Institut Universitaire d'Hématologie, Université Paris Diderot, Sorbonne Paris Cité, 75010 Paris, France;
authors.forename: Sophie
authors.initials: S
authors.lastname: Agaugué
authors.affiliation: Laboratoire d'Immunologie et Histocompatibilité, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, 75010 Paris, France;
authors.forename: Guylaine
authors.initials: G
authors.lastname: Henry
authors.affiliation: INSERM, Unité Mixte de Recherche-S1172, 59045 Lille, France; Laboratoire d'Hématologie, Centre de Biologie-Pathologie Centre Hospitalier Régional Universitaire Lille, Université de Lille, 59000 Lille, France;
authors.forename: Meyling
authors.initials: M
authors.lastname: Cheok
authors.affiliation: INSERM, Unité Mixte de Recherche-S1160, 75010 Paris, France; Institut Universitaire d'Hématologie, Université Paris Diderot, Sorbonne Paris Cité, 75010 Paris, France;
authors.forename: Marguerite
authors.initials: M
authors.lastname: Vignon
authors.affiliation: Institut Universitaire d'Hématologie, Université Paris Diderot, Sorbonne Paris Cité, 75010 Paris, France; Laboratoire d'Hématologie Biologique, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, 75010 Paris, France; Tumorothèque, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, 75010 Paris, France;
authors.forename: Daniela
authors.initials: D
authors.lastname: Geromin
authors.affiliation: Institut Universitaire d'Hématologie, Université Paris Diderot, Sorbonne Paris Cité, 75010 Paris, France; Laboratoire d'Hématologie Biologique, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, 75010 Paris, France; Tumorothèque, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, 75010 Paris, France;
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Cayuela
authors.affiliation: Université de Versailles-Saint Quentin, 78000 Versailles, France;
authors.forename: Sylvie
authors.initials: S
authors.lastname: Castaigne
authors.affiliation: Université Paris-Est Créteil, 94000 Créteil, France; Service d'Hématologie Clinique, Assistance Publique-Hôpitaux de Paris, Hôpital Henri Mondor, 94000 Créteil, France;
authors.forename: Cécile
authors.initials: C
authors.lastname: Pautas
authors.affiliation: Service d'Hématologie Adulte, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, 75010 Paris, France; Université Paris Diderot, Sorbonne Paris Cité, EA3518, 75010 Paris, France;
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Raffoux
authors.affiliation: INSERM, Unité Mixte de Recherche-S1052, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; Centre National pour la Recherche Scientifique, Unité Mixte de Recherche-5286, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; Université Unité Mixte de Recherche-S1052, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; Université de Lyon, 69000 Lyon, France; and ProfileXpert, 69008 Lyon, France.
authors.forename: Joel
authors.initials: J
authors.lastname: Lachuer
authors.affiliation: Institut Universitaire d'Hématologie, Université Paris Diderot, Sorbonne Paris Cité, 75010 Paris, France;
authors.forename: François
authors.initials: F
authors.lastname: Sigaux
authors.affiliation: INSERM, Unité Mixte de Recherche-S1172, 59045 Lille, France; Laboratoire d'Hématologie, Centre de Biologie-Pathologie Centre Hospitalier Régional Universitaire Lille, Université de Lille, 59000 Lille, France;
authors.forename: Claude
authors.initials: C
authors.lastname: Preudhomme
authors.affiliation: Institut Universitaire d'Hématologie, Université Paris Diderot, Sorbonne Paris Cité, 75010 Paris, France; Service d'Hématologie Adulte, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, 75010 Paris, France; Université Paris Diderot, Sorbonne Paris Cité, EA3518, 75010 Paris, France;
authors.forename: Hervé
authors.initials: H
authors.lastname: Dombret
authors.affiliation: INSERM, Unité Mixte de Recherche-S1160, 75010 Paris, France; Institut Universitaire d'Hématologie, Université Paris Diderot, Sorbonne Paris Cité, 75010 Paris, France; Laboratoire d'Immunologie et Histocompatibilité, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, 75010 Paris, France; nicolas.dulphy@univ-paris-diderot.fr antoine.toubert@univ-paris-diderot.fr.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dulphy
authors.affiliation: INSERM, Unité Mixte de Recherche-S1160, 75010 Paris, France; Institut Universitaire d'Hématologie, Université Paris Diderot, Sorbonne Paris Cité, 75010 Paris, France; Laboratoire d'Immunologie et Histocompatibilité, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, 75010 Paris, France; nicolas.dulphy@univ-paris-diderot.fr antoine.toubert@univ-paris-diderot.fr.
authors.forename: Antoine
authors.initials: A
authors.lastname: Toubert
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D005260:Female; D059805:HLA-DR alpha-Chains / Q000276:immunology; D059811:HLA-DRB1 Chains / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D019409:Interleukin-15 / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology*; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D019718:Receptors, CXCR4 / Q000096:biosynthesis; D017471:Receptors, Interferon / Q000096:biosynthesis; D055607:Receptors, Natural Killer Cell / Q000378:metabolism*; D012799:Sialyltransferases / Q000276:immunology; D019139:Tumor Escape / Q000235:genetics / Q000276:immunology*; D055815:Young Adult; D000096743:Interferon gamma Receptor; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase
chemical_list: D015703:Antigens, CD; D015815:Cell Adhesion Molecules; D059805:HLA-DR alpha-Chains; D059811:HLA-DRB1 Chains; D007371:Interferon-gamma; D019409:Interleukin-15; D019718:Receptors, CXCR4; D017471:Receptors, Interferon; D055607:Receptors, Natural Killer Cell; D012799:Sialyltransferases; D000096743:Interferon gamma Receptor; C527276:CXCR4 protein, human; C086185:IFNGR2 protein, human; C569274:IL15 protein, human; C093493:ST6GAL1 protein, human; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase