Two-layered immune escape in AML is overcome by Fcγ receptor activation and inhibition of PGE₂ signaling in NK cells

Loss of anticancer natural killer (NK) cell function in patients with acute myeloid leukemia (AML) is associated with fatal disease progression and remains poorly understood. Here, we demonstrate that AML blasts isolated from patients rapidly inhibit NK cell function and escape NK cell-mediated killing. Transcriptome analysis of NK cells exposed to AML blasts revealed increased CREM expression and transcriptional activity, indicating enhanced cyclic adenosine monophosphate (cAMP) signaling, confirmed by uniform production of the cAMP-inducing prostanoid prostaglandin E₂ (PGE₂) by all AML-blast isolates from patients. Phosphoproteome analysis disclosed that PGE₂ induced a blockade of lymphocyte-specific protein tyrosine kinase (LCK)–extracellular signal-regulated kinase signaling that is crucial for NK cell activation, indicating a 2-layered escape of AML blasts with low expression of NK cell-activating ligands and inhibition of NK cell signaling. To evaluate the therapeutic potential to target PGE₂ inhibition, we combined Fcγ-receptor-mediated activation with the prevention of inhibitory PGE₂ signaling. This rescued NK cell function and restored the killing of AML blasts. Thus, we identify the PGE₂-LCK signaling axis as the key barrier for NK cell activation in 2-layered immune escape of AML blasts that can be targeted for immune therapy to reconstitute anticancer NK cell immunity in patients with AML.