Two-layered immune escape in AML is overcome by Fcγ receptor activation and inhibition of PGE2 signaling in NK cells
Abstract
Abstract 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.
Article Details
Authors (30)
Charlotte Rothfuß
1Institute of Molecular Immunology, School of Medicine and Health, Technical University of Munich, Munich, Germany
Tobias Baumann
1Institute of Molecular Immunology, School of Medicine and Health, Technical University of Munich, Munich, Germany
Sainitin Donakonda
1Institute of Molecular Immunology, School of Medicine and Health, Technical University of Munich, Munich, Germany
Bettina Brauchle
2Gene Center, Laboratory for Translational Cancer Immunology, Ludwig-Maximilians-Universität München, Munich, Germany
Anetta Marcinek
2Gene Center, Laboratory for Translational Cancer Immunology, Ludwig-Maximilians-Universität München, Munich, Germany
Christian Urban
3Institute of Virology, School of Medicine and Health, Technical University of Munich, Munich, Germany
Julia Mergner
Anna-Marie Pedde
1Institute of Molecular Immunology, School of Medicine and Health, Technical University of Munich, Munich, Germany
Anna Hirschberger
1Institute of Molecular Immunology, School of Medicine and Health, Technical University of Munich, Munich, Germany
Christina Krupka
2Gene Center, Laboratory for Translational Cancer Immunology, Ludwig-Maximilians-Universität München, Munich, Germany
Anne-Sophie Neumann
4Gene Center, Laboratory for Translational Cancer Immunology, Ludwig-Maximilians-Universität München, Munich, Germany
Gerulf Hänel
Ludwig Maximilian University Hospital, Munich, Germany
Camilla Merten
5Institut of Molecular and Clinical Immunology, Otto-von-Guericke-Universität Magdeburg, Magdeburg, Germany
Rupert Öllinger
Judith S. Hecker
Tanja Bauer
3Institute of Virology, School of Medicine and Health, Technical University of Munich, Munich, Germany
Christian Schmid
Katharina S. Götze
Jennifer Altomonte
9Department of Internal Medicine II, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany
Veit Bücklein
Ludwig Maximilian University Hospital, Munich, Germany
Roland Jacobs
10Department of Rheumatology and Clinical Immunology, Hannover Medical School, Hannover, Germany
Roland Rad
Corina Dawid
8Food Chemistry and Molecular Sensory Science, Technical University of Munich, Munich, Germany
Luca Simeoni
5Institut of Molecular and Clinical Immunology, Otto-von-Guericke-Universität Magdeburg, Magdeburg, Germany
Burkhart Schraven
5Institut of Molecular and Clinical Immunology, Otto-von-Guericke-Universität Magdeburg, Magdeburg, Germany
Andreas Pichlmair
Marion Subklewe
Ludwig Maximilian University Hospital, Munich, Germany
Percy A. Knolle
Jan P. Böttcher
Bastian Höchst
1Institute of Molecular Immunology, School of Medicine and Health, Technical University of Munich, Munich, Germany