The diacylglycerol kinase inhibitor ASP1570 augments natural killer cell function

The enhancement of T cell and NK cell function is an immunotherapeutic strategy for combating cancer. Anti-bodies that block inhibitory receptors, such as PD-1 and CTLA4, augment T cell function and have been suc-cessful in curing patients with some types of cancer. As an alternative approach to targeting specific inhibitory receptors by antibodies, small molecule drugs that inhibit negative regulators of T cell activation have been sought. One potential pharmacological target is diacylglycerol (DAG) kinase (DGK)zeta, which is an enzyme that acts as a negative regulator of DAG by phosphorylating DAG and converting it into phosphatidic acid. DAG-mediated signaling is critical for T cell activation through its T cell receptor and NK cell activation down-stream of a variety of activating receptors. Thus, DGK zeta-deficient T cells and NK cells display increased function upon activating receptor engagement. Moreover, treatment with the DGK zeta-selective inhibitor ASP1570 augments T cell function. In this study, we sought to test whether the acute inhibition of DGK zeta by ASP1570 augments NK cell function. We find that ASP1570 enhances DAG-mediated signaling in immunoreceptor-stimulated NK cells. Accordingly, ASP1570 treatment enhanced IFN gamma production and degranulation of immunoreceptor-activated NK cells in vitro and NK cell-mediated tumor clearance in vivo. Thus, ASP1570 enhances both T and NK cell function, which could possibly induce more durable anti-tumor responses for immunotherapy.