Abstract 1180: Asparagine deprivations enhance CD8+ T cell antitumor activity and ICB immunotherapy via ROS-mediated NFAT nuclear localization

Abstract Metabolic reprogramming plays a crucial role in the differentiation and activation of T cells. Both oxidative phosphorylation (OXPHOS) and glycolysis are upregulated to meet the high energy demands. However, the impact of amino acid metabolism on T cell activation remains unclear. Our study demonstrates that asparagine deprivation enhances the antitumor activity of CD8+ cytotoxic T lymphocytes (CTLs) and increases the flux of glycolysis and the tricarboxylic acid (TCA) cycle. Mechanistically, asparagine deprivation induces the production of reactive oxygen species (ROS) through mitochondrial complex I deficiency and leads to nuclear localization of NFAT, subsequently affecting cytokine production and T cell activation. In the animal model, we found that the clinical drug leunase exhibits antitumor activity that relies on the immune response of T cells. Leunase treatment promotes the activation of tumor-infiltrating lymphocytes (TILs) in vivo. Furthermore, the combination therapy of leunase and anti-PD1 demonstrates a synergistic effect. In patients with nasopharyngeal carcinoma (NPC), leunase therapy enhances the cytokines production and activation of CD8+ T cell. In summary, our findings offer valuable insights into how T cells adapt to changes in their nutritional environment. Citation Format: Hsuan Chia Chang, Kwang-Huei Lin, Huang Yu Yang. Asparagine deprivations enhance CD8+ T cell antitumor activity and ICB immunotherapy via ROS-mediated NFAT nuclear localization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1180.