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.

PROJECT NARRATIVE Substantial drug resistance of lymphoma patients to current immunotherapeutic regimens is linked to the immunosuppressive tumor microenvironment that depletes the white blood lymphocytes (T cells) of essential nutrients and causes their exhaustion during the T cell-mediated anti-lymphoma immune response. Targeting the branched chain amino acid metabolism is a new and exciting opportunity to offer a metabolic intervention to support T cell survival under conditions that limit their performance. This metabolic intervention aims to offer an improved immunotherapeutic approach that will be highly applicable in treating lymphoma patients.