Inhibiting fatty acid synthesis (FAS) can prevent and treat chronic graft versus host disease (cGVHD)

Abstract

Abstract GVHD remains the primary complication of allogeneic hematopoietic stem cell transplantation. Considerable interest exists in understanding how metabolism affects immune cell function. We show targeting FAS represents an attractive strategy to ameliorate cGVHD. Acetyl-CoA carboxylase 1 (ACC1) catalyzes the first step of FAS, and can be pharmacologically inhibited with either Soraphen A or 5-(Tetradecyloxy)-2-furoic acid (TOFA). FAS is critical for T cell effector responses, a finding we confirmed using an in vivo multiorgan system cGVHD model with bronchiolitis obliterans, a model dependent on germinal centers (GC), IgG2c secretion, lung deposition and fibrosis. Compared to wild type T cells, cGVHD mice receiving CD4CreACC1fl/fl allogeneic T cells had reduced cGVHD severity assessed by pulmonary function test and immune phenotyping. As thymic regulatory T cell (tTreg) infusion can prevent and treat cGVHD, we examined tTreg FAS needs. Inhibiting FAS in sorted tTreg via drug (Soraphen A; TOFA) or genetic (FoxP3CreACC1fl/fl) strategies increased oxidative and glycolytic metabolism measured by Seahorse assay, that correlated with superior in vitro suppressor function. These findings were extended in vivo where transfer of FoxP3CreACC1fl/fl tTreg, at day 28 following disease establishment, decreased cGVHD severity. Daily treatment of cGVHD mice from day 28 to day 56 with TOFA reversed cGVHD. An in vitro assay in which T follicular regulatory cells suppress T follicular helper and GC B cell class switching showed that inhibiting tTreg FAS can increase their suppression of GC responses. These data provide evidence that inhibiting FAS can prevent or treat cGVHD and enhance Treg function, providing a new approach to ameliorate cGVHD.