| First Author | Arranz-Nicolás J | Year | 2020 |
| Journal | J Immunother Cancer | Volume | 8 |
| Issue | 2 | PubMed ID | 33246984 |
| Mgi Jnum | J:343057 | Mgi Id | MGI:7562619 |
| Doi | 10.1136/jitc-2020-001521 | Citation | Arranz-Nicolas J, et al. (2020) Diacylglycerol kinase zeta limits IL-2-dependent control of PD-1 expression in tumor-infiltrating T lymphocytes. J Immunother Cancer 8(2) |
| abstractText | 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 Ca(2+)-regulated transcriptional programs. In mice, DAG kinase zeta (DGKzeta) facilitates DAG consumption, limiting T cell activation and cytotoxic T cell responses. DGKzeta deficiency facilitates tumor rejection in mice without apparent adverse autoimmune effects. Despite its therapeutic potential, little is known about DGKzeta 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 DGKzeta depletion on the transcriptional restriction imposed by PD-1 ligation. We studied the effect of DGKzeta deficiency on PD-1 expression dynamics, as well as the impact of DGKzeta absence on the in vivo growth of MC38 adenocarcinoma cells. RESULTS: We demonstrate that DGKzeta depletion enhances DAG-regulated transcriptional programs, promoting interleukin-2 production and partially counteracting PD-1 inhibitory functions. DGKzeta 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 DGKzeta-deficient mice. CONCLUSIONS: Our results, which define a role for DGKzeta in the control of PD-1 expression, confirm DGKzeta potential as a therapeutic target as well as a biomarker of CD8(+) T cell dysfunctional states. |
