The diacylglycerol kinase ζ inhibitor ASP1570 augments natural killer cell function

Abstract

The enhancement of T cell and NK cell function is an immunotherapeutic strategy for combating cancer. Antibodies that block inhibitory receptors, such as PD-1 and CTLA4, augment T cell function and have been successful 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)ζ, 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 downstream of a variety of activating receptors. Thus, DGKζ-deficient T cells and NK cells display increased function upon activating receptor engagement. Moreover, treatment with the DGKζ-selective inhibitor ASP1570 augments T cell function. In this study, we sought to test whether the acute inhibition of DGKζ by ASP1570 augments NK cell function. We find that ASP1570 enhances DAG-mediated signaling in immunoreceptor-stimulated NK cells. Accordingly, ASP1570 treatment enhanced IFNγ 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.

Keywords: DAG; DGK inhibitor; DGKζ; ERK; NK cells.