Targeting temporal metabolic needs of T follicular helper cells to treat cGVHD utilizing a mitochondrial pyruvate carrier inhibitor

Abstract

Abstract The curative potential of allogeneic hematopoietic stem cell transplantation is limited by development of chronic graft versus host disease (cGVHD) and metabolic regulation of immune cells is a promising therapeutic target. During cGVHD, interactions between T follicular helper (TFH) and germinal center B (GCB) cells result in production of alloreactive class-switched antibodies that attack host tissues, causing multi-organ damage and tissue fibrosis. We show the metabolic dependencies of TFH change throughout cGVHD progression and targeting mitochondrial pyruvate transport is an effective strategy to mitigate disease. Pyruvate, the end product of glycolysis, is transported by the mitochondrial pyruvate carrier (MPC) for use in the tricarboxylic acid cycle and oxidative phosphorylation (OXPHOS). TFH require glycolysis in order to induce a GC reaction, both in an immunization model and in an in vivo systemic cGVHD model with bronchiolitis obliterans (BO). Furthermore, Seahorse data from TFH extracted early in disease development in the BO model demonstrate increased dependency on glycolysis. But Seahorse data also indicates TFH undergo a shift away from glycolysis and toward OXPHOS as cGVHD continues. Based on the central role of MPC in tying pyruvate to multiple metabolic pathways, we examined an inhibitor of MPC (7ACC1) in reducing TFH activity. Administration of 7ACC1 resulted in inhibition of GCB production of class switched antibody in an in vitro assay. These findings were additionally supported in vivo, whereby daily treatment after establishment of cGVHD resulted in a decrease in disease severity. These data provide evidence that inhibiting mitochondrial pyruvate transport is a viable therapeutic strategy for cGVHD. This work was supported by grants from National Institutes of Health, National Institute of Allergy, and Infectious Diseases R37 AI34495, T32 AI007313; National Heart, Lung, and Blood Institute R01 HL56067, R01 HL11879, R01 HL115114 ; National Cancer Institute P01 CA065493