Diacylglycerol Kinases (DGKs): Novel Targets for Improving T Cell Activity in Cancer

Abstract

Diacylglycerol kinases (DGKs) are a family of enzymes that catalyze the metabolism of diacylglycerol (DAG). Two isoforms of DGK, DGKα, and DGKζ, specifically regulate the pool of DAG that is generated as a second messenger after stimulation of the T cell receptor (TCR). Deletion of either isoform in mouse models results in T cells bearing a hyperresponsive phenotype and enhanced T cell activity against malignancy. Whereas, DGKζ appears to be the dominant isoform in T cells, rationale exists for targeting both isoforms individually or coordinately. Additional work is needed to rigorously identify the molecular changes that result from deletion of DGKs in order to understand how DAG contributes to T cell activation, the effect of DGK inhibition in human T cells, and to rationally develop combined immunotherapeutic strategies that target DGKs.

Keywords: CD8+ T cell; T cell receptor; diacylglycerol; diacylglycerol kinase; immunotherapy.

Figure 1

Model of enhanced T cell activity in DGK-deficient T cells. DGKα and DGKζ function to metabolize DAG generated downstream of TCR activation. Deletion of either or both isoforms results in T cells with enhanced TCR signal transduction downstream of DAG and resultant enhanced effector functions (“No inhibitor”). Loss of DGK confers resistance to inhibitory pathways that function through direct interference of TCR signal transduction, since these inhibitory events occur proximal to generation of DAG (“Direct TCR Inhibitor”). We predict that T cells deficient in DGKs remain sensitive to inhibitory pathways that mediate their effect independent of interference with TCR signal transduction (“Non-TCR Inhibitor”), or for pathways that inhibit TCR signaling at rate limiting steps downstream of DAG formation.