PuSH - Publication Server of Helmholtz Zentrum München: Two-layered immune escape in AML is overcome by Fcγ receptor activation and inhibition of PGE2 signaling in NK cells.

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Rothfuß, C.* ; Baumann, T.* ; Donakonda, S.* ; Brauchle, B.* ; Marcinek, A.* ; Urban, C.* ; Mergner, J.* ; Pedde, A.M.* ; Hirschberger, A.* ; Krupka, C.* ; Neumann, A.S.* ; Hänel, G.* ; Merten, C.* ; Öllinger, R.* ; Hecker, J.S.* ; Bauer, T. ; Schmid, C.R.* ; Götze, K.S.* ; Altomonte, J.* ; Bücklein, V.L.* ; Jacobs, R.* ; Rad, R.* ; Dawid, C.* ; Simeoni, L.* ; Schraven, B.* ; Pichlmair, A.* ; Subklewe, M.* ; Knolle, P.A.* ; Böttcher, J.P.* ; Höchst, B.*

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

Blood 145, 1395-1406 (2025)

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Loss of anticancer NK cell function in AML patients 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 cAMP signalling, confirmed by uniform production of the cAMP-inducing prostanoid PGE2 by all AML-blast isolates from patients. Phosphoproteome analysis disclosed that PGE2 induced a blockade of LCK-ERK signalling that is crucial for NK cell activation, indicating a two-layered escape of AML-blasts with low expression of NK cell-activating ligands and inhibition of NK cell signalling. To evaluate the therapeutic potential to target PGE2 inhibition, we combined Fcg-receptor-mediated activation with the prevention of inhibitory PGE2-signalling. This rescued NK cell function and restored the killing of AML-blasts. Thus, we identify the PGE2-LCK signalling axis as the key barrier for NK cell activation in two-layered immune escape of AML-blasts that can be targeted for immune therapy to reconstitute anti-cancer NK cell immunity in AML patients.

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