Control of GVHD and Leukemia Relapse by Targeting Cell Metabolism

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 DESCRIPTION (provided by applicant): Allogeneic bone marrow transplantation (allo-BMT) is an effective therapy for hematologic malignancies through T cell-mediated graft-versus-leukemia (GVL) effects, but allogeneic T cells often lead to severe graft-versus-host disease (GVHD) as well. Because GVHD and tumor relapse are two major concerns when allo-BMT is used as a therapy for hematologic malignancies, the broad and long-term goal of our research is to prevent GVHD and tumor relapse, which would greatly enhance the therapeutic potential of allo-BMT. Glycolysis and oxidative phosphorylation (OXPHOS) are two basic cellular metabolic pathways to generate of adenosine-5'triphosphate (ATP) as a source of energy. Because OXPHOS generates ATP with high efficiency, normal cells rely on OXPHOS for ATP under normoxia conditions, and only switch to glycolysis under hypoxic conditions. However, malignant cells primarily utilize glycolysis for energy production even under normoxia conditions, known as aerobic glycolysis. Similar to malignant cells, activated T cells also switch to glycolysi to acquire sufficient energy. Cell metabolism plays a key role in T-cell activation, differentiatio and function, which is essential for the induction of GVHD. As a consequence, targeting T-cell metabolic pathways to control GVHD has recently become an interesting strategy. However, very little is known about T-cell metabolic pathways under allogeneic BMT. The objective of this project is to understand the metabolic pathways of T cells after being transplanted into allogeneic recipients, and to identify/validate potential targets on T-cell metabolic pathways in controlling GVHD as well as tumor relapse. The central hypothesis is that a certain metabolic pathway likely within glycolysis is shared by pathogenic T cells and malignant cells such as leukemia, and thus targeting this specific pathway will control T-cell mediated GVHD and prevent leukemia relapse. To determine T-cell metabolic pathways (Aim 1), we will use and metabolomics technology to define the complex biochemical processes of T cells under allogeneic responses in vivo, and to identify metabolic processes or products as potential targets to specifically inhibit T-cell allogeneic responses. Using Seahorse bioenergetics approach, our preliminary study has shown that T cells after allogeneic BMT dramatically increased aerobic glycolysis, and blocking glycolysis by genetically ablating mammalian target of rapamycin (mTOR) essentially prevented GVHD. Thus, we will further validate glycolic pathway as potential target in controlling GVHD and leukemia relapse (Aim 2). Using preclinical murine models of allogeneic BMT and leukemia, we will determine whether targeting glycolic pathway is effective in controlling GVHD and leukemia relapse.