EPIGENETIC DYSFUNCTION OF TERMINALLY EXHAUSTED TUMOR INFILTRATING T CELLS

T lymphocytic as datasets from deficiency facilitates tumor rejection in mice without apparent adverse autoimmune effects. In spite of its therapeutic potential, little is known about DGK z function in human T cells and there are not iso-form-specific inhibitors targeting this DGK isoform. Methods Here we used of a human triple parameter reporter (TPR) cell line to examine the consequences of DGK z depletion in the transcriptional restriction imposed by PD-1 liga-tion. We also investigated the effect of DGK z deficiency in the expression dynamics of PD-1, as well as the impact of the absence of this DGK isoform in the in vivo growth of a MC38 adenocarcinoma cell line. Results We demonstrate that DGK z depletion enhances DAG-regulated transcriptional programs, favoring IL-2 production and limiting PD-1 expression. Diminished PD-1 expression and enhanced expansion of cytotoxic CD8+ T cell popula-tions is also observed even in the context of immunosuppres-sive milieus and correlates with the failure of MC38 adenocarcinoma cells to form tumors in DGK z -deficient mice. Conclusions Our results suggest the relevance of DGK z as a therapeutic target on its own as well as a biomarker of CD8 + T cell dysfunctional states.