Imbalanced activating and inhibitory receptors on cd56dim natural killer cells predicts poor outcomes in acute myeloid leukemia

Even with advances in understanding the physiopathology of Acute Myeloid Leukemia (AML), most patients still relapse leading to poor long-term prognosis and cure rates. Natural Killer (NK) cells are regulated by opposing signals from receptors that activate and inhibit effector function and are known to mediate anti-leukemic immunosurveillance in AML, but the mechanisms by which they control hematopoietic neoplasms remain unclear. We hypothesize that functionally impaired NK cells can predict poor outcomes in AML. We analyzed the expression of DNAM-1 and NKG2D (activating) and NKG2A and KIR2DL1 (inhibitory) receptors on CD56+, CD56bright CD16- and CD56dim CD16+NK subsets, by flow cytometry, in 100 de novo AML bone marrow (BM), followed up from 02/2016 to 06/2022, 17 healthy BM (HBM) and 6 BM from remission after induction chemotherapy (AML-CR). Correlations with ELN2017 risk, complete remission (CR), relapse (R), measurable residual disease (MRD), overall survival (OS), and relapse-free survival (RFS) were verified. Co-culture of AML-exposed NK cells and K562 cell line was used to assay for killing and degranulation. Proteomics and genomics were accessed by CITE-seq single-cell sequencing. All NK cell subsets were decreased in AML (p < .01). AML CD56+ NK cells showed decreased NKG2D (p