Targeting medium chain fatty acid metabolism for the treatment of chronic Graft-versus-Host Disease

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Abstract Chronic graft versus host disease (cGVHD) has emerged as one of the major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). However, there is limited therapeutic option for cGVHD prevention and therapy. Steroid, the standard initial therapy of cGVHD, often is unsuccessful in preventing permanent organs damage and has been associated with significant toxicities. Fatty acid (FA) metabolism decides T cell (Tc) fate and function in cGVHD development. However, how medium chain fatty acid (MCFA) participates in cGVHD pathobiology has not been studied. GPR84 has been well known as the MCFA sensing receptor. Using peripheral blood nonnuclear cells (PBMCs) and fecals from cGVHD patients along with murine models of cGVHD, we elucidate the implication of GPR84 signaling in cGVHD pathobiology. The scientific premise of current research proposal is to understand how GPR84- mediated MCFA signaling regulates T cell metabolism in cGVHD and therefore validate GPR84 targeting as an effective approach to control cGVHD. In Aim 1, we will elucidate the biological function of GPR84-mediated MCFA metabolism in cGVHD. We will use GPR84 genetically knockout mice and MCFA- enriched diet to understand the role of MCFA signaling in bronchiolitis obliterans (BO)-, and thymus-damaged cGVHD. In Aim 2, we will elucidate mechanisms responsible for the impact of GPR84- mediated MCFA signaling in cGVHD pathobiology. Utilizing stable isotope-resolved metabolomics, high dimensional flow cytometry, and single cell ATAC-seq, we will validate how GPR84 signaling by regulating cellular metabolism would influence Tc and follicular helper Tc (TFH) survival, migration, differentiation, and function. We will elucidate the function CD8+T follicular cells (TFC), which is found enriched in cGVHD patient’s PBMCs and elucidate how GPR84 signaling regulates this novel cell subset post- transplant. In Aim 3, we investigate whether GPR84 targeting would be a therapeutic option for cGVHD while preserving the GVL effect. We will use a combination of pharmacological antagonist; CRISPR-cas9 induced gene silencing, and diet programming approaches with human-to-mouse cGVHD model to test our hypothesis. We will also examine if GPR84 targeting would be effective in the prevention steroid refractory cGVHD. Because GPR84 inhibitor GLPG1205 has been found safe and effective in phase 2 clinical; precise dietaries and microbiome- modulating therapies are important in the treatment of cGVHD, current research proposal is highly translational and critically important.