Kureshi et al. demonstrated that dual DGKα/ζ inhibition enhanced priming and antigen-specific effector functions of CD8+ T cells with different affinities (TRP1high and TRP1low) in vitro and in vivo. The effect was most pronounced in situations where TCR affinity or avidity were suboptimal. DGKi-mediated cytotoxicity was dependent on MHC-I and IFNγ expression, but not on perforin. DGKi increased proliferation and cytokine production in antigen-specific T cells in mice bearing C2VTrp1 tumors (low Trp1 expression) and synergized with anti-PD-1 therapy to control melanoma and pancreatic tumor growth in an antigen-dependent manner.
Contributed by Shishir Pant
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.
Author Info: (1) Department of Immunology, Harvard Medical School, Boston, MA, USA. Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. (2) Department o
Author Info: (1) Department of Immunology, Harvard Medical School, Boston, MA, USA. Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. (2) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA. (3) Department of Immunology, Harvard Medical School, Boston, MA, USA. Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. (4) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA. (5) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. (6) Department of Immunology, Harvard Medical School, Boston, MA, USA. Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. (7) Department of Immunology, Harvard Medical School, Boston, MA, USA. Department of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA. (8) Bristol Myers Squibb, Cambridge, MA, USA. (9) Bristol Myers Squibb, Cambridge, MA, USA. (10) Department of Immunology, Harvard Medical School, Boston, MA, USA. Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
