Regulation of NK cell chemotaxis by KCa3.1 channels

Abstract

Abstract CD8+ T cells and NK cells are the primary line of defense against tumor cells. However, the tumor microenvironment impairs their anti-tumor capabilities. One of the key functions impaired is the ability of T and NK cells to infiltrate the tumor, essential to allow the direct contact with a target cell and its killing. Kv1.3 and KCa3.1 K +channels have a multitude of essential functions that have been established in CD8+ T cells: Kv1.3 regulates cytotoxicity and KCa3.1 chemotaxis. However, less is known about K +channels in NK cells. Herein, we performed electrophysiological and 3D chemotaxis experiments to study the activity and functional role of K +channels in human NK cells. NK cells were isolated from healthy donors (HD) and head and neck cancer (HNC) patients and activated with IL-2 and IL-15 for 24–48 hr. Activation led to an increase in Kv1.3 currents of 49.6% at 24 hr and 434.1% at 48 hr . KCa3.1 activity increased by 42.8% at 24 hr and 54.2% at 48 hr. Chemotaxis experiment showed that activated NK cells move randomly in the collagen matrix and migrated towards the chemokine gradient in presence of CXCL10. Chemotaxis, but not random migration, was inhibited by the selective KCa3.1 blocker TRAM-34 in NK cells from HD and HNC patients. Shk-Dap22, a Kv1.3 blocker, did not alter either chemotaxis or random migration. Overall, TRAM-34 reduced the distance achieved by NK cells in the chemokine gradient by 157% in HD (4 donors) and 89% in HNC NK cells (1 donor). These data highlight the critical role of KCa3.1 channels in NK cell migration and open the possibility of targeting KCa3.1 to facilitate tumor infiltration by NK cells.