Deciphering Human NK Cell Development and Function in Health and in Blood Malignancies to Improve NK Cell-Based Therapy Against Cancer

Natural Killer (NK) cells are innate lymphocytes responsible for protection against cancer. Patients with leukemia often acquire NK-cell dysfunctions; the mechanism behind these impairments is not well understood and the contribution of diseased bone marrow (BM) environment remains unexplored. We have recently established an in vitro culture system that faithfully recapitulates human NK cell development. In the proposed studies, we will apply this platform to define key pathways controlling human NK cell development and effector functions, using specific knockdown by short hairpin RNA (shRNA), and testing how their disruption in hematopoietic progenitors affects NK cell differentiation and activity. Using RNA sequencing of cells generated in these cultures, we will identify receptor-ligand pairs to characterize interactions between NK cells and their environment during differentiation. We will then determine how these regulatory pathways are altered during disease by gene expression analysis (RNA-sequencing of samples from MDS and AML patients). To address whether our in vitro NK cell developmental model is compatible with their in vivo differentiation, we will establish a humanized ossicle mouse model. This new model will allow to study NK cell development in vivo and to investigate involvement of diseased BM environment in the disease-induced NK cell defects. These studies will provide a better understanding of NK cell development and effector functions in heath and in disease to improve NK cell-based therapies.