Elucidating the role of the Branched Chain Aminotransferases (BCATc and BCATm) as novel metabolic checkpoints of anti-lymphoma T cell immunity

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PROJECT SUMMARY New immunotherapies targeting lymphomas delivered promising results during recent clinical trials. However, these therapies were only effective in a small subset of patients with short periods of remission. The results from these studies suggested the existence of immunosuppression in the tumor microenvironment. Indeed, the lymphoma microenvironment is a very dynamic network between lymphoma cells and non-malignant components that may promote tumor growth and consequently drug resistance. Progress in T cell metabolism has demonstrated that T cells experience a metabolic disadvantage in the tumor microenvironment, which often manifests in T cell exhaustion that jeopardizes their potential to destroy cancer cells. This reveals a critical need to explore new (metabolic) approaches to improve T cell performance. Our research team proposes to target the metabolism of the branched chain amino acids (BCAAs) as a novel metabolic checkpoint of T cell activation in the lymphoma microenvironment. Our rationale stems from the findings that the BCAA, leucine, is indispensable for T cells activation, while BCAA metabolism, initiated by the cytosolic (BCATc) and mitochondrial (BCATm) branched-chain aminotransferases, is a means to direct leucine toward degradation. The objective in this application is to determine whether a loss of expression of BCATc and BCATm is beneficial for the durability and functional integrity of T cells during lymphoma eradication in unique pre-clinical mouse models created in our laboratory. The long-term goal of this application is to provide new means to improve the T cell-mediated immune response and to address the challenges with T cell-driven anti-lymphoma immunotherapy. The central hypothesis is that BCATc, supported by BCATm, serves to provide checkpoint control on T cell function by being a part of a negative feedback loop regulation of T cell activation. Deletion of the BCAT genes from T cells, individually or in combination, may provide a metabolic advantage of T cells allowing them to remain activated and to successfully combat lymphoma growth. To test the central hypothesis, we identified three specific aims: (1) Investigate how the expression of BCATc and BCATm changes upon T cell subset differentiation and whether the BCAT proteins are essential for T cell lineage commitment and function, (2) Determine whether a blockage in the transamination of BCAAs enhances the T cell response to lymphoma tumors, and (3) Investigate whether a loss of expression of BCATc in mouse T cells can overcome the lymphoma resistance to anti-CTLA4 therapy. Completion of this project will not only provide the opportunity to improve the current treatment options for lymphoma patients but will also engage students in pre-clinical cancer studies. The students will highly benefit from acquiring hands-on research experience in cancer, which can be translated into enhanced research skills, scientific reasoning, and better understanding of treatment approaches.