DGKα/ζ inhibition lowers the TCR affinity threshold and potentiates anti-tumor immunity

Checkpoint blockade immunotherapies expand neoantigen- or virus-specific T cells, and poor responsiveness to immunotherapy is associated with lower mutational burden in tumors of non-viral origin. Although mouse models demonstrate that lower affinity T cells recognizing self-antigens can contribute to tumor control if sufficiently activated, therapeutic options for enhancing T cell priming are limited. Diacylglycerol kinases (DGKs) attenuate DAG signaling by converting DAG to phosphatidic acid, thereby suppressing pathways downstream of TCR signaling. Using a novel dual DGK alpha and zeta inhibitor (DGKi), tumor-specific CD8 T cells with different affinities (TRP1high and TRP1low), and a series of 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 IL-2, IFNγ, and other effector cytokines in the presence of cognate antigen and DGKi. Effector TRP1high- and TRP1low-mediated c..., Methods used are described in detail in the manuscript., , # Data from: DGKα/ζ inhibition lowers the TCR affinity threshold and potentiates anti-tumor immunity

Data for Kureshi et al

Raw Quantitative values for all the figure data sets. Each sheet is labeled with the corresponding figures and corresponding panels are labeled in bold font.

Figure 1. Inhibition of DGKα/ζ in antigen-specific CD8 T cells enhances proliferation and cytokine production in a dose-dependent manner.
Panel A & B. Trp1high CD8 T cells were activated with αCD3/28 antibodies for 5,15,30, and 60 minutes and western blot was conducted for phosphorylated and total ERK1/2 levels. Band intensity values from imageJ are provided in the Excel sheet.

Panel C. Trp1high Cd8 T cells were activated with B cells pulsed with 0, 50, and 500pg/mL peptide at denoted concentrations of DGK inhibitor. Proliferation indices are provided in the Excel sheet and was calculated from CTV staining. Fold change in proliferation was calculated in reference to vehicle-treated group for each pepti...