Abstract SY12-04: Lowering the TCR signaling threshold with a DGKa/z dual inhibitor potentiates anti-tumor immunity

Abstract

Abstract 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) suppress DAG signaling by converting DAG to phosphatidic acid, thereby attenuating pathways downstream of TCR signaling. Using a novel dual DGKa/z 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 DGKa/z can lower the signaling threshold for T cell priming. TRP1high and TRP1low CD8 T cells produced more IL-2 and IFNγ in the presence of cognate antigen and DGKi. Effector TRP1high- and TRP1low-mediated cytolysis of tumor cells with low antigen load was MHC-restricted, mediated by IFNg and augmented by DGKi. Adoptive T cell transfer into mice bearing pancreatic or melanoma tumors synergized with single-agent DGKi or DGKi and αPD1, with increased expansion of low affinity T cells and increased cytokine production observed in tumor infiltrates of treated mice. Collectively, our findings highlight DGKa/z as therapeutic targets for augmenting tumor-specific CD8 T cell function. Citation Format: Stephanie K. Dougan. Lowering the TCR signaling threshold with a DGKa/z dual inhibitor potentiates anti-tumor immunity. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr SY12-04.