Rothfuß Charlotte, Baumann Tobias, Donakonda Sainitin, Brauchle Bettina, Marcinek Anetta, Urban Christian, Mergner Julia, Pedde Anna-Marie, Hirschberger Anna, Krupka Christina, Neumann Anne-Sophie, Hänel Gerulf, Merten Camilla, Öllinger Rupert, Hecker Judith S, Bauer Tanja, Schmid Christian, Götze Katharina S, Altomonte Jennifer, Bücklein Veit, Jacobs Roland, Rad Roland, Dawid Corina, Simeoni Luca, Schraven Burkhart, Pichlmair Andreas, Subklewe Marion, Knolle Percy A, Böttcher Jan P, Höchst Bastian
Institute of Molecular Immunology, School of Medicine and Health, Technical University of Munich, Munich, Germany.
Gene Center, Laboratory for Translational Cancer Immunology, Ludwig-Maximilians-Universität München, Munich, Germany.
Blood. 2025 Mar 27;145(13):1395-1406. doi: 10.1182/blood.2024025706.
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.
急性髓系白血病（AML）患者抗癌自然杀伤（NK）细胞功能丧失与致命的疾病进展相关，目前对此仍知之甚少。在此，我们证明从患者分离出的AML原始细胞可迅速抑制NK细胞功能并逃避NK细胞介导的杀伤。对暴露于AML原始细胞的NK细胞进行转录组分析，发现CREM表达和转录活性增加，表明环磷酸腺苷（cAMP）信号增强，这一点通过患者所有AML原始细胞分离株均能均匀产生诱导cAMP的前列腺素前列腺素E2（PGE2）得到证实。磷酸化蛋白质组分析显示，PGE2诱导淋巴细胞特异性蛋白酪氨酸激酶（LCK）-细胞外信号调节激酶信号传导受阻，而该信号传导对NK细胞激活至关重要，这表明AML原始细胞通过低表达NK细胞激活配体和抑制NK细胞信号传导实现了两层逃逸。为评估靶向抑制PGE2的治疗潜力，我们将Fcγ受体介导的激活与预防抑制性PGE2信号传导相结合。这挽救了NK细胞功能并恢复了对AML原始细胞的杀伤。因此，我们确定PGE2-LCK信号轴是AML原始细胞两层免疫逃逸中NK细胞激活的关键障碍，可将其作为免疫治疗靶点，以重建AML患者的抗癌NK细胞免疫。
