Defining the role of Acss2 in T cell adaptation to metabolic stress - PROJECT SUMMARY The metabolic characteristics of the tumor microenvironment, including hypoxia and nutrient depletion, create major barriers to anti-tumor immune responses and immunotherapy. As such, mechanisms by which T cells adapt to these challenging conditions are of significant clinical interest. Recent studies have demonstrated that certain forms of metabolic restriction promote a stem-like, long-lived T cell phenotype characterized by robust upregulation of acetyl-CoA synthetase 2 (Acss2). While most studies of Acss2 have focused on its metabolic role in the cytoplasm, Acss2 has been shown in cancer cells to translocate into the nucleus in response to metabolic stress and facilitate targeted gene expression by providing acetyl-CoA for histone acetylation. Acss2 therefore functions as a metabolic sensor for extracellular nutrient and oxygen levels and integrates this information with epigenetically driven changes in gene expression. Despite high levels of expression in T cells, the role of Acss2 in T cell function and antitumor immunity has not been well-defined. Our preliminary data demonstrates that genetic loss of Acss2 causes T cells to proliferate excessively and further increases activation in conditions of hypoxic stress. Furthermore, in a mouse model of acute bacterial infection, Acss2 knockout T cells hyperexpand and hyperactivate compared to wild-type counterparts. However, in an antigenic tumor model, loss of Acss2 results in the marked depletion of antigen-specific tumor infiltrating lymphocytes. Based on these data, we hypothesize that Acss2 acts as a previously uncharacterized metabolic checkpoint that restrains T cell activation and prevents hyperactivation-induced cell death under conditions of metabolic stress. We propose to test this hypothesis through the following aims: Aim 1: Characterizing the subcellular localization and function of Acss2 in T cells exposed to culture conditions mimicking the TME; Aim 2: Assessing the epigenetic role of Acss2 in T cells and its impact on immunotherapy outcomes. These aims will be achieved through a combination of immunology, cell biology, and sequencing-based approaches in primary murine T cells and syngeneic tumor models. This work is significant because it will elucidate the role of Acss2 in CD8 T cell immunity and uncover novel therapeutic targets to improve response rates to cancer immunotherapies.
