Thursday, November 21, 2024
11/21/2024
PROJECT SUMMARY Metabolism is a key driver of T cell functions, and the switch from oxidative-phosphorylation to aerobic glycolysis is a hallmark of T cell activation. Unfortunately, tumor reactive T cells often display a compromised metabolic status due to metabolic competition with cancer cells within the tumor microenvironment (TME). Therefore, strategies to enhance metabolic fitness of T cells within the metabolically challenging tumor bed may rescue resistance to existing cancer immunotherapies. In this context, we have focused on the regulation of T cell metabolism by Sirt2, an NAD-dependent histone deacetylase. Our preliminary data demonstrate that Sirt2 functions as a metabolic checkpoint that harnesses T cell effector functions and impairs anti-tumor immunity. Specifically, upregulation of Sirt2 expression in human tumor-infiltrating T lymphocytes (TILs) negatively correlates with response to Nivolumab and TIL therapy in non-small cell lung cancer. Mechanistically, Sirt2 suppresses glycolysis and oxidative-phosphorylation by deacetylating key metabolic enzymes. Accordingly, Sirt2-deficient T cells manifest increased glycolysis and oxidative-phosphorylation, display enhanced proliferation and effector functions, and have superior anti-tumor activity. Importantly, pharmacologic inhibition of Sirt2 endows human TILs with these superior metabolic fitness and enhanced effector functions. These findings indicate targeting Sirt2 may allow reprogramming of T cell metabolism to augment a broad spectrum of cancer immunotherapies. Guided by this scientific premise we propose the overall hypothesis that Sirt2 activity governs the metabolic fitness of T cells at tumor beds, and therefore controls the magnitude of immune pressure against malignant progression. We will test this hypothesis in the following specific aims: Aim 1 will investigate the precise molecular mechanisms via which Sirt2 regulate glycolysis, TCA cycle, glutaminolysis and fatty acid oxidation, and the post-translational mechanisms that govern Sirt2 expression and function in tumor-reactive T cells. Aim 2 will explore the metabolic functions of Sirt2 in physiologic contexts of T cells during activation, differentiation, maturation and as they are subjected to metabolic constraints within the tumor beds. Aim 3 will determine the metabolic and immunologic consequences of Sirt2 inhibition in human TILs for clinical translation, and correlate Sirt2 expression in TILs with response to immunotherapy. These aims will be achieved by employing a variety of experimental strategies involving in vitro and in vivo metabolic and immunologic analyses of various genetically engineered animals, complemented by molecular biology and genetic studies using primary human T cells and patient-derived TILs from lung cancer and melanoma. Collectively, our proposed studies will provide a comprehensive view of the role of Sirt2-regulated metabolic processes in tumor-reactive T cells. The results from our proposed studies will validate Sirt2 as an actionable metabolic and immunologic target, and Sirt2 inhibition will be a tractable means to improve cancer immunotherapy.
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