Epigenetic Regulation of T Cell Metabolism and Immune Functions by Sirt6

PROJECT SUMMARY Cancer immunotherapy represents a major paradigm shift in cancer care. Despite such breakthrough, most cancer patients remain refractory to these therapies. Metabolism is a key driver of T cell functions, and the metabolic switch from oxidative phosphorylation to aerobic glycolysis is a hallmark of T cell activation. Unfortunately, tumor-reactive T cells often display a compromised metabolic activity due to nutrient competition with cancer cells at tumor bed. Therefore, strategies to rewire the metabolic fitness of T cells within the unfavorable microenvironment of tumors are expected to rescue the resistance to existing cancer immunotherapies. In this context, this proposal aims to understand the epigenetic mechanisms priming the metabolic switch in T cells under metabolic stress via Sirt6, an NAD+-dependent histone deacetylase. The preliminary data of this study establish Sirt6 as an epigenetic silencer of T cell metabolism that impairs T cell effector functions. Specifically, Sirt6 expression is upregulated in murine melanoma tumor-infiltrating T lymphocytes (TILs), and Sirt6 blockade increases their glycolytic activity and enhances their effector functions. Mechanistically, Sirt6 deacetylates histone H3K9 to repress the transcription of the glycolytic genes, thus directing glucose away from the glycolytic pathway, the metabolic program that is required for effective anti- tumor immune response. Accordingly, Sirt6 deficiency in murine T cells leads to an upregulation of glycolytic genes’ transcription with increased glycolytic rate, subsequently resulting in superior anti-tumor activity following tumor challenge in vivo. Importantly, Sirt6 blockade endows human TILs from non-small cell lung cancer patients with superior metabolic fitness and enhanced effector functions. These findings indicate that targeting Sirt6 may lead to boosting T cell metabolism to augment a broad spectrum of cancer immunotherapies. Guided by this scientific premise, the overall hypothesis of this study states that Sirt6 restrains the metabolic activity and effector response of T cells at tumor bed via chromatin remodeling, thus facilitating cancer immune escape. This hypothesis will be evaluated by the following specific aims: Aim 1 will investigate the precise epigenetic mechanisms via which Sirt6 regulates chromatin remodeling and metabolic reprogramming in T cells. Aim 2 will determine the immunologic consequences of Sirt6 inhibition in T cells against tumor challenge in Patient-Derived Xenograft mouse models for translational application. These aims will be reached by employing a multitude of experimental strategies involving in vitro epigenetic, metabolic, and immunologic analyses using primary mouse and human T cells, complemented by in vivo studies using genetically engineered patient-derived TILs and their autologous tumors. Collectively, the proposed studies will provide a comprehensive view of the epigenetic role of Sirt6 in metabolic processes in tumor-reactive T cells. The results from these studies will validate Sirt6 as an actionable metabolic and immunologic target with tractable means to improve cancer immunotherapy.