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.

Survival in acute myeloid leukemia is associated with NKp44 splice variants

“…[12-14, 44] The NKp44 receptor, along with the NKp46 and NKp30 receptors, belongs to the NCRs, which are predominantly expressed in innate lymphoid cells and are important activating receptors on pNK cells. [19, 22] In previous studies of NKp46 and NKp30 expression in AML patients, down-regulation of their expression was linked to impaired NK cell function and poor prognosis, while up-regulation was associated with enhanced NK cell function and better prognosis of the AML patients.…”

“…[19, 22] In previous studies of NKp46 and NKp30 expression in AML patients, down-regulation of their expression was linked to impaired NK cell function and poor prognosis, while up-regulation was associated with enhanced NK cell function and better prognosis of the AML patients. [14, 44] In contrast, although NKp44 expression was studied on NK cells from AML patients, a possible link between AML immunity and NKp44 expression by NK cells was not previously reported. [14] The current study analyzed NKp44 expression and AML prognosis.…”

“…[5–11] It has been previously shown that the status of NK cells in AML is critical for patients’ survival and that AML leukemic cells can induce impaired NK cell function. [12–14] NK cell function is regulated through a delicate balance of activation vs. inhibitory signals that is sustained by an array of cell surface receptors engaging ligands on target cells. [15] While activation receptors (e.g.…”

Variable Natural Killer Cell Activity in Hematological Malignancies at Diagnosis

“…NKA has been proposed as an immunological surrogate marker in patients with hematological malignancies and as a predictor of the effect of anticancer therapy [9,10]. In AML, NK cytotoxicity and effector cytokine function were restored following induction chemotherapy [25]. AML patients with defective NK cells had a signi cantly higher risk of relapse [25].…”

“…In AML, NK cytotoxicity and effector cytokine function were restored following induction chemotherapy [25]. AML patients with defective NK cells had a signi cantly higher risk of relapse [25]. MM patients showed a decreased NKA with advanced clinical stage, and patients with a high NKA after chemotherapy showed better survival than patients with a low NKA [26].…”