NK receptor ligand expression impacts outcomes after chemotherapy in AML

Natural killer (NK) cells play an important role in the elimination of malignant cells, including leukemic blasts. These cells’ effector functions are dependent on the balance of activating and inhibitory receptor-ligand interactions. Sara Mastaglio and Eric Wong from the Royal Melbourne Hospital, Melbourne, Australia, and colleagues analyzed the impact of the differential expression of activating and inhibitory NK receptor ligands (NKRLs) by leukemic blasts on clinical outcomes of  newly diagnosed Acute Myeloid Leukemia (AML) patients who underwent induction chemotherapy. The results were published ahead of print in Blood Advances on 15 February 2018.

Cryopreserved bone marrow aspirate samples from 66 patients (median age at diagnosis = 56, range 16 – 78) with newly diagnosed AML who underwent induction chemotherapy were obtained from the Australasian Leukemia and Lymphoma Group tissue bank and analyzed in this study. Expression (by relative fluorescence intensity [RFI]) of six activating (MICA, MICAB, CD155, CD112, ULBP1, and ULBP2/5/6) and three inhibitory (HLA class I, PD-L1, and PD-L2) NKRLs was analyzed by flow cytometry.

Key findings:

Among activating ligands, MICA (78.8%), CD112 (80.3%), and ULBP1 (81.8%) were frequently expressed by AML blasts and displayed the highest intensity of expression (median RFI of 3, 4.2, and 6.5, respectively).

• When analyzed individually, only ULBP1 had a prognostic impact
• Compared to ULBP1 negative AML blasts, 2-year Overall Survival (OS) and Relapse Free Survival (RFS) was better in patients with ULBP1 positive AML blasts: 51.4% vs4%, P = 0.05 and 42.5% vs 10.0%, P = 0.05, respectively
• 2-year Cumulative Incidence of Relapse (CIR) in ULBP1 positive and negative patients: 44.1% vs6%, P = 0.005
• Patients with the highest ULBP1 expression had a reduced Hazard Ratio (HR) of death (HR = 0.22, P = 0.05) or relapse (HR = 0.18, P = 0.05) compared to non-expressing patients

In order to reflect the combinatorial effect of multiple NKRLs, a flow cytometry net score of activating minus inhibitory ligands was calculated, which stratified patients into 2 groups: G0 (inhibitory pattern [n = 32]) and G1 (activating pattern [n = 34]).

• 2-year OS in the G1 and G0 cohort: 59.6% vs4%, HR = 0.46; P < 0.05
• 2-year RFS in the G1 and G0 group: 51.5% vs8%, HR = 0.52; P = 0.05
• 2-year CIR in the G1 and G0 cohort: 31.5% vs2%, HR = 0.36; P < 0.05
• The G1 phenotype remained significantly associated with lower CIR when taking into account either CG or ELN risk.

AML patients with intermediate cytogenetics demonstrated an activating pattern of NKRL expression and had significantly better survival and lower CIR compared with patients with an inhibitory NKRL pattern.

In summary, expression of activating NKRLs by AML blasts is associated with a better survival and reduced relapse following induction chemotherapy. The authors noted that their results suggest that NKRLs may represent a novel prognostic tool for new diagnosed AML particularly in patients with intermediate risk cytogenetics. They further concluded by suggesting that AML blasts are effective targets for NK cell-mediated immune surveillance, and investigation into therapeutic strategies to enhance NK cell activation as a means of maintaining remission is warranted.