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Front Immunol. 2017 May 29;8:573. doi: 10.3389/fimmu.2017.00573. eCollection 2017.

Natural Killer Defective Maturation Is Associated with Adverse Clinical Outcome in Patients with Acute Myeloid Leukemia.

Author information

1
Team Immunity and Cancer, Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, U1068; CNRS, UMR7258, Institut Paoli-Calmettes; Aix-Marseille University, UM 105, Marseille, France.
2
Immunomonitoring platform, Institut Paoli-Calmettes, Marseille, France.
3
Hematology Department, Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, U1068; CNRS, UMR7258, Institut Paoli-Calmettes; Aix-Marseille University, UM 105, Marseille, France.
4
Beckman Coulter Immunotech, Marseille, France.
5
Systems Biology Platform, Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, U1068; CNRS, UMR7258, Institut Paoli-Calmettes; Aix-Marseille University, UM 105, Marseille, France.
6
Biostatistics and methodology department, CHU Angers, Angers, France.
7
Hematology department, CHU Angers, Angers, France.
8
GOELAMStheque, FILO (French Innovative Leukemia Organization), Cochin Hospital, APHP, Paris, France.
9
Laboratoire d'Hématologie, Centre Hospitalier Universitaire de Reims, Reims, France.
10
Service d'Hématologie, Centre Catherine de Sienne, Nantes, France.
11
INSERM UMRS-1160, Univ Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Immunology and Histocompatibility department, Hôpital Saint-Louis, APHP, Paris, France.
12
Centre d'Immunophénomique - CIPHE (PHENOMIN), Aix Marseille University, UMS3367; Inserm US012; CNRS, UMS3367, Marseille, France.
13
Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université UM2, Inserm U1104, CNRS UMR7280, F-13288, Marseille, France.
14
Biopathology Department, Institut Paoli Calmettes, Marseille, France.

Abstract

Accumulating evidence highlights natural killer (NK) cell parameters as potential prognostic factors in cancer patients, which provides a strong rationale for developing therapeutic strategies aiming at restoring NK cell. However, reaching this point warrants better characterization of tumor-induced NK cell alterations. Our group recently reported heterogeneous NK maturation in acute myeloid leukemia (AML) patients. However, the clinical significance of such observations remained to be assessed on a larger cohort of patients. NK maturation based on expression of CD56, CD57, and KIR was assessed by flow cytometry in newly diagnosed AML patients (N = 87 patients from GOELAMS-LAM-IR-2006 multicenter trial). Clinical outcome was evaluated with regard to NK maturation profiles. Unsupervised integrated analysis of NK maturation markers confirmed the existence of three distinct groups of patients [hypomaturation (24.1%), intermediate maturation (66.7%), and hypermaturation (9.2%)]. In univariate analysis, significant differences in overall survival (OS) (P = 0.0006) and relapse-free survival (RFS) (P < 0.0001) were observed among these different groups. Patients with hypomaturation profile had reduced OS, with 3-year OS rates of 12.5 vs 57.1 and 57.4% for patients with intermediate and hypermaturation, respectively. Consistently, patients with hypomaturation profile had reduced RFS, with 3-year RFS rates of 0 vs 52.6 and 73.3% for patients with intermediate and hypermaturation, respectively. In multivariate Cox regression models, NK hypomaturation remained significantly associated with reduced OS and RFS, independent of other factors [hazard ratio (HR) = 4.15, P = 0.004 and HR = 8.23, P = 0.003, respectively]. NK maturation defects were further explored by mass cytometry and revealed that NK hypomaturation profile is associated with a reduced frequency of memory-like NK cells. In conclusion, besides classical alterations of NK triggering and inhibitory receptors expression in AML, we confirm that the homeostasis of NK maturation can be modified in the context of AML, notably with a deep maturation blockade in almost 10% patients.

KEYWORDS:

acute myeloid leukemia; mass cytometry; natural killer; natural killer maturation; prognostic biomarkers

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