Dgk Zeta Exerts Greater Control Than Dgk Alpha Over Cd8(+) T Cell Activity And Tumor Inhibition

Two isoforms of diacylglycerol kinases (DGKs), DGK alpha and DGK zeta, are primarily responsible for terminating DAG-mediated activation of Ras and PKC theta pathways in T cells. A direct comparison of tumor growth between mice lacking each isoform has not been undertaken. We evaluated the growth of three syngeneic tumor cell lines in mice lacking either DGK alpha or DGK zeta in the presence or absence of treatment with anti-PD1 and determined that (i) mice deficient in DGK zeta conferred enhanced control of tumor relative to mice deficient in DGK alpha and (ii) deficiency of DGK zeta acted additively with anti-PD1 in tumor control. Consistent with this finding, functional and RNA-sequencing analyses revealed greater changes in stimulated DGK zeta-deficient T cells compared with DGK alpha-deficient T cells, which were enhanced relative to wildtype T cells. DGK zeta also imparted greater regulation than DGK alpha in human T cells. Together, these data support targeting the zeta isoform of DGKs to therapeutically enhance T cell anti-tumor activity.