title: Deficient expression of NCR in NK cells from acute myeloid leukemia: Evolution during leukemia treatment and impact of leukemia cells in NCRdull phenotype induction.
abstract: Natural killer (NK) cells play an important role in tumor-cell clearance, particularly against leukemia, as shown by killer cell inhibitory receptor (KIR)-mismatched allogeneic stem cell transplantation. Analysis of in vitro IL-2-expanded NK cells from patients with myelocytic/monocytic acute myeloid leukemia (AML-NK cells) has revealed poor cytolytic functions because of deficient expression of pivotal activation molecules-the natural cytotoxicity receptors (NCRs) NKp30, NKp44, and NKp46. To exclude the possibility that this observation was caused by the in vitro amplification of a small NCR(dull) population, we analyzed the AML-NK phenotype directly, without any in vitro expansion. We first confirmed that the NCR(dull) phenotype was not an in vitro artifact. Moreover, analysis of a large population of AML patients allowed us to demonstrate that phenotype was not restricted to a French-American-British (FAB) subtype and was not associated with a particular cytogenetic abnormality. Our longitudinal study of AML patients showed that the NCR(dull) phenotype was acquired during leukemia development because we observed its complete (for NKp46) or partial (for NKp30) reversibility in patients achieving complete remission (CR). Reversibility of the NCR(dull) phenotype after CR suggested that leukemia cells might be involved in NCR down-regulation. In agreement with this hypothesis, direct contact between leukemic blasts and NK cells (but not leukemia-cell supernatants) induced loss or decrease in NKp30 and NKp46 expression while impeding NKp44 induction by IL-2. We excluded the major implication of TGF-beta in NCR down-regulation. Although the clinical antitumor value of NK cells is clearly demonstrated in allogeneic stem cell transplantation, the role of NK cells in autologous transplantation is not proved. Interestingly, we observed a correlation between the NCR(dull) phenotype and poor survival in AML patients, suggesting that NK-deficient activation caused by NCR down-regulation could play a role in patient outcome. The prognostic value of NCR expression is discussed, and pathophysiologic implication of the NCR phenotype will be further investigated in a larger study.
authors.affiliation: Laboratoire d'Immunologie des Tumeurs, Institut National de la Santé et de la Recherche Médicale (INSERM) Unite Mixté de Recherche (UMR) 599, Marseille, France.
authors.forename: Cyril
authors.initials: C
authors.lastname: Fauriat
authors.forename: Sylvaine
authors.initials: S
authors.lastname: Just-Landi
authors.forename: Françoise
authors.initials: F
authors.lastname: Mallet
authors.forename: Christine
authors.initials: C
authors.lastname: Arnoulet
authors.forename: Danielle
authors.initials: D
authors.lastname: Sainty
authors.forename: Daniel
authors.initials: D
authors.lastname: Olive
authors.forename: Regis T
authors.initials: RT
authors.lastname: Costello
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002454:Cell Differentiation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D053208:Kaplan-Meier Estimate; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism*; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000172:deficiency* / Q000235:genetics; D008875:Middle Aged; D055627:Natural Cytotoxicity Triggering Receptor 1; D055629:Natural Cytotoxicity Triggering Receptor 2; D055628:Natural Cytotoxicity Triggering Receptor 3; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000502:physiology; D011971:Receptors, Immunologic / Q000096:biosynthesis* / Q000172:deficiency* / Q000235:genetics; D012074:Remission Induction; D016019:Survival Analysis; D014407:Tumor Cells, Cultured / Q000737:chemistry
chemical_list: D007376:Interleukin-2; D008562:Membrane Glycoproteins; C112260:NCR1 protein, human; C112837:NCR2 protein, human; C431710:NCR3 protein, human; D055627:Natural Cytotoxicity Triggering Receptor 1; D055629:Natural Cytotoxicity Triggering Receptor 2; D055628:Natural Cytotoxicity Triggering Receptor 3; D009363:Neoplasm Proteins; D011971:Receptors, Immunologic