DGKα/ζ inhibition lowers the TCR affinity threshold and potentiates antitumor immunity
Rakeeb Kureshi, Elisa Bello, Courtney T.S. Kureshi, Michael J. Walsh, Victoria Lippert, Megan T. Hoffman, Michael Dougan, Tyler A. Longmire, Michael Wichroski, Stephanie K. Dougan
Abstract
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 DGKα/ζ inhibitor (DGKi), tumor-specific CD8 T cells with different affinities (TRP1 high and TRP1 low ), and altered peptide ligands, we demonstrate that inhibition of DGKα/ζ 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-γ, 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 DGKα/ζ as therapeutic targets for augmenting tumor-specific CD8 T cell function.