Abstract
Abstract Background: Studies of diacylglycerol kinase ζ (DGKζ) in DGKζ-knockout mice have revealed its role as an intracellular immune checkpoint in T cells. Although enhancing antitumor immunity by pharmacological inhibition of DGKζ is desirable, selective DGKζ inhibitors for clinical use remain largely unexplored. Here, we report a novel, small-molecule, DGKζ inhibitor—ASP1570—which is currently under phase 1 development (NCT05083481), and describe its nonclinical properties and potential application in cancer immunotherapy. Methods: ASP1570 was characterized by evaluating T cell receptor signaling and T cell function under immunosuppressive conditions relevant to the tumor microenvironment. Antitumor efficacy was evaluated in 2 types of syngeneic mouse models: anti-PD-1-antibody–sensitive MC38 and anti-PD-1-antibody–insensitive B16F1/F10. Results: ASP1570 enhanced T cell activation with increased diacylglycerol downstream signaling and released anergic T cells from their hyporesponsive state. Further, ASP1570 restored T cell functions suppressed by multiple immunosuppressive signals (TGF-β, prostaglandin E2, adenosine, PD-1, CTLA-4, and TIGIT) and induced tumor-growth inhibition in MC38 and B16F1/F10 syngeneic mouse models. The antitumor efficacy of ASP1570 was cancelled by CD8+ T cell depletion, indicating that its antitumor effect depends on CD8+ cytotoxic T cell activation. Conclusions: ASP1570 potentially improves antitumor efficacy in both anti-PD-1-therapy–resistant and anti-PD-1-therapy–responsive tumors by overcoming multiple immunosuppressive signals. Citation Format: Osamu Ikeda, Aya Kikuchi, Hirofumi Tsuzuki, Toshihiro Matsuda, Jane Weng, Tomoko Kawashima, Tetsuo Kiso, Atsushi Suzuki, Takeyuki Nagashima, Tomoyuki Suzuki, Kazuya Yamano, Taku Yoshida. Enhanced antitumor immunity by ASP1570 in mouse models: A novel DGKζ inhibitor offers a potential immunotherapy for treating cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A004.
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