Cord Blood Natural Killer Cells Exhibit Impaired Lytic Immunological Synapse Formation That Is Reversed with IL-2 Ex Vivo Expansion

Peripheral blood natural killer (NK) cell therapy for acute myeloid leukemia has shown promise in clinical trials after allogeneic stem cell transplantation (SCT). Cord blood (CB) is another potentially rich source of NK cells for adoptive immune therapy after SCT. Tightly regulated receptor signaling between NK cells and susceptible tumor cells is essential for NK cell-mediated cytotoxicity. However, despite expressing normal surface activating and inhibitory NK receptors, CB-derived NK cells have poor cytolytic activity. In this study, we investigate the cellular mechanism and demonstrate that unmanipulated CB-NK cells exhibit an impaired ability to form F-actin immunological synapses with target leukemia cells compared with peripheral blood-derived NK cells. In addition, there was reduced recruitment of the activating receptor CD2, integrin LFA-1, and the cytolytic molecule perforin to the CB-NK synapse site. Ex vivo IL-2 expansion of CB-NK cells enhanced lytic synapse formation including CD2 and LFA-1 polarization and activity. Furthermore, the acquired anti-leukemic function of IL-2-expanded CB-NK cells was validated using a NOD-SCID-IL2Rγ null mouse model. We believe our results provide important mechanistic insights for the potential use of IL-2-expanded CB-derived NK cells for adoptive immune therapy in leukemia.