Diacylglycerol Kinase Zeta Limits Il-2-Dependent Control Of Pd-1 Expression In Tumor-Infiltrating T Lymphocytes

Background The inhibitory functions triggered by the programmed cell death-1 (PD-1) receptor following binding to its ligand (PD-L1) protect healthy organs from cytotoxic T cells, and neutralize antitumor T cell attack. Antibody-based therapies to block PD-1/PD-L1 interaction have yielded notable results, but most patients eventually develop resistance. This failure is attributed to CD8(+) T cells achieving hyporesponsive states from which recovery is hardly feasible. Dysfunctional T cell phenotypes are favored by a sustained imbalance in the diacylglycerol (DAG)- and Ca2+-regulated transcriptional programs. In mice, DAG kinase zeta (DGK zeta) facilitates DAG consumption, limiting T cell activation and cytotoxic T cell responses. DGK zeta deficiency facilitates tumor rejection in mice without apparent adverse autoimmune effects. Despite its therapeutic potential, little is known about DGK zeta function in human T cells, and no known inhibitors target this isoform. Methods We used a human triple parameter reporter cell line to examine the consequences of DGK zeta depletion on the transcriptional restriction imposed by PD-1 ligation. We studied the effect of DGK zeta deficiency on PD-1 expression dynamics, as well as the impact of DGK zeta absence on the in vivo growth of MC38 adenocarcinoma cells. Results We demonstrate that DGK zeta depletion enhances DAG-regulated transcriptional programs, promoting interleukin-2 production and partially counteracting PD-1 inhibitory functions. DGK zeta loss results in limited PD-1 expression and enhanced expansion of cytotoxic CD8(+) T cell populations. This is observed even in immunosuppressive milieus, and correlates with the reduced ability of MC38 adenocarcinoma cells to form tumors in DGK zeta-deficient mice. Conclusions Our results, which define a role for DGK zeta in the control of PD-1 expression, confirm DGK zeta potential as a therapeutic target as well as a biomarker of CD8(+) T cell dysfunctional states.