Mimicking the bone marrow niche – 3D culture as a new tool to improve NK cell-based immunotherapies for AML

Acute myeloid leukemia (AML) is a hematopoietic malignancy characterized by overproduction of myeloid precursors and stem cells. Although novel targeted therapies have been developed, relapse continues to be a significant concern. Natural killer (NK) cell immunotherapy holds promise to counteract the disease relapse. As AML is a bone marrow-residing malignancy it is especially relevant to understand the interaction of NK cells with leukemic cells in this niche in order to enhance the effectiveness of NK cell adoptive transfer therapies. The main aim of this project is the establishment of a 3D coculture system to evaluate NK cell-based immunotherapies for AML in an environment mimicking the bone marrow niche. This approach could serve as a preliminary stage for in vivo experiments, thereby reducing the need for animal experiments. Our model will be the first to study the influence of mesenchymal stem cells, a crucial regulatory cell type in the bone marrow niche, on AML cell evasion from NK cells. Via establishing a complex 3D tumor microenvironment, we will investigate mechanisms how the bone marrow niche facilitates the evasion of AML cells from NK cells, as detailed transcriptome characterization on single cell level, complemented by secretome analysis from 3D triculture is our second goal. In the future such an approach will allow for the exploration of novel strategies to enhance NK cell killing of leukemic cells and gain deeper insights into the mechanisms underlying their evasion from NK cell-mediated cytotoxicity. On the long run this strategy could serve as a high throughput personalized platform to test the susceptibility of primary AML blasts to allogenic NK cells. Joining the expertise in 3D cultures of the University of Continuing Education together with the long-standing expertise in NK cell biology and AML of the Division Pharmacology, Karl Landsteiner University of Health Sciences, is a unique opportunity to pursue this interdisciplinary project.