DGKα/ζ inhibition lowers the TCR affinity threshold and potentiates antitumor immunity

Diacylglycerol kinases (DGKs) attenuate diacylglycerol (DAG) signaling by converting DAG to phosphatidic acid, thereby suppressing pathways downstream of T cell receptor signaling. Using a dual DGK alpha/zeta inhibitor (DGKi), tumor-specific CD8 T cells with different affinities (TRP1(high) and TRP1(low)), and altered peptide ligands, we demonstrate that inhibition of DGK alpha/zeta can lower the signaling threshold for T cell priming. TRP1(high) and TRP1(low) CD8 T cells produced more effector cytokines in the presence of cognate antigen and DGKi. Effector TRP1(high)- and TRP1(low)-mediated cytolysis of tumor cells with low antigen load required antigen recognition, was mediated by interferon-gamma, and augmented by DGKi. Adoptive T cell transfer into mice bearing pancreatic or melanoma tumors synergized with single-agent DGKi or DGKi and antiprogrammed cell death protein 1 (PD-1), with increased expansion of low-affinity T cells and increased cytokine production observed in tumors of treated mice. Collectively, our findings highlight DGK alpha/zeta as therapeutic targets for augmenting tumor-specific CD8 T cell function.