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

Sci Adv. 2023 Nov 24;9(47):eadk1853. doi: 10.1126/sciadv.adk1853. Epub 2023 Nov 24.

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 (TRP1high and TRP1low), and altered peptide ligands, we demonstrate that inhibition of DGKα/ζ can lower the signaling threshold for T cell priming. TRP1high and TRP1low CD8 T cells produced more effector cytokines in the presence of cognate antigen and DGKi. Effector TRP1high- and TRP1low-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.

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes
  • Diglycerides* / metabolism
  • Mice
  • Neoplasms*
  • Receptors, Antigen, T-Cell / metabolism
  • Signal Transduction

Substances

  • Diglycerides
  • Receptors, Antigen, T-Cell