Role of Ca2+-activated KCa3.1 potassium channel in CAR T cell effector function

Abstract Genetically modified chimeric antigen receptor (CAR) T cells eliminate tumors by recognizing specific antigens on the cell surface. T cell ion channels (e.g. Kv1.3, KCa3.1) influence activation, proliferation, and effector functions such as target cell killing, through the regulation of Ca2+ signaling. We showed that CAR-expressing cells (Jurkat) specifically eliminate tumor cells (Raji B cells) in monolayer culture and inhibition of KCa3.1 by TRAM34 increased the tumor cell–killing ability of KCa3.1+ Jurkat CARs. Blockage of KCa3.1 facilitated the migration of KCa3.1+ Jurkat CARs (mean speed, displacement and distance). The application of TRAM34 lowered the baseline Ca2+ level in mCherry-KCa3.1+ Jurkat CARs. Finally, TRAM34 significantly reduced the time needed to eliminate tumor cells. We concluded that expression and modification of KCa3.1 ion channels shifts the intracellular Ca2+ concentration into the range where cytotoxicity dominates. Hence, modification of KCa3.1 channels could contribute to a more effective anticancer immunotherapy.