Natural killer receptor ligand expression on acute myeloid leukemia impacts survival and relapse after chemotherapy

Abstract

Natural killer (NKs) cells provide rapid responses to viral-infected and malignant cells, including acute myeloid leukemia (AML) blasts. The balance among inhibitory and activating signals, delivered by multiple interactions between ligands on target cells and NK receptors, determines the posture of the NK cell response to either one of target cell elimination or tolerance. The aim of this work was to study the influence of the differential expression of activating and inhibitory NK receptor ligands (NKRLs) by leukemic blasts on clinical outcome in newly diagnosed AML patients. Leukemic cells and clinical data from 66 patients undergoing induction chemotherapy were obtained from the Australasian Leukemia Lymphoma Group tissue bank. Expression of 6 activating (MICA, MICAB, CD155, CD112, ULBP1, and ULBP2/5/6) and 3 inhibitory (HLA class I, PD-L1, and PD-L2) NKRLs was analyzed by flow cytometry. AML blasts displayed heterogeneous expression of NKRLs. MICA, CD112, and ULBP1 were most frequently expressed. ULBP1 expression was significantly associated with improved 2-year overall survival (51.4% vs 11.4%), relapse-free survival (42.5% vs 10.0%), and reduced relapse (44.1% vs 78.6%). We calculated a net score of activating minus inhibitory ligands and demonstrated that the expression of an overall activating NK ligand phenotype was associated with superior 2-year overall survival (59.6% vs 24.4%) and reduced relapse (31.5% vs 68.2%). Our study provides clinical evidence for the role of NK cell-mediated immunoediting against AML, mediated by the expression of NKRLs on blasts, and supports investigation into strategies to enhance NK cell function to improve outcomes in patients with AML.

Boosting Natural Killer Cell-Mediated Targeting of Sarcoma Through DNAM-1 and NKG2D

“…DNAM-1 + GM NK-92 cells degranulated against all primary sarcoma explants as well as against the majority of the established cell lines, proving the potential of CD112 and CD155 as tumorspecific markers for targeted immunotherapies (Figures 3, 7). This, along with the absence of the degranulation response of NK cells against healthy donor PBMCs, showed that the use of DNAM-1 + GM NK-92 cells could be restricted/directed only to targets that had elevated CD112 and/or CD155 expression (Figures 2, 7), which is observed in tumors from various origins (65)(66)(67)(68)(69)(70)(71)(72)(73)(74)(75)(76)(77)(78)(79)(80)(81)(82)(83), including osteosarcomas (24).…”

Genetic and Molecular Basis of Heterogeneous NK Cell Responses against Acute Leukemia

“…On the basis of clinical data, NK cells appear to play a crucial role in the eradication of acute leukemia [ 26 , 27 , 28 ]. However, the ability of NK cells to mediate a response against tumor cells such as leukemia cells depends on the presence of ligands that are recognized by NK receptors on tumor cells [ 12 , 13 , 26 , 29 ]. In this study, a broad diversity of NK cell responses was observed in vitro against myeloid and lymphoid cell lines.…”

“…Cognate ligands are heterogeneously expressed on leukemias. It has been reported that the absence of expression or downregulation of HLA class I molecules, as well as the presence of activating ligands on the surface of leukemia cells, were associated with the reduction of relapse incidence and improved overall survival of patients with leukemia [ 12 , 13 ].…”

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

“…Interestingly, there appears to be large variability in the anti-leukemic effects of 293C3-SDIE, possibly due to differing expression patterns of CD133 between patients. This may also be in part due to evidence of HLA dimorphism and NK cell ligand expression impacting AML therapy (244,245). Furthermore, as described above, autologous patient NK cells may have been functionally impaired, relative to allogeneic NK cells (176).…”