Rebalancing T cell response in allogeneic hematopoietic stem cell transplant by targeting monocarboxylate metabolism 2557

Description Allogeneic hematopoietic stem cell transplantation is limited by acute graft-versus-host disease (aGVHD), caused by alloreactive donor T cell damage to host tissues. We targeted monocarboxylate transporter 1 (MCT1) based on its role in lactate efflux, T cell metabolism and proliferation. In vitro cultured MCT1 knockout (KO) vs wildtype (WT) T cells had reduced proliferation and higher mitochondrial respiration along with an increased lactate dehydrogenase (LDH)B to LDHA ratio. MCT1 KO T cells had elevated expression of Treg associated antigens and H3K27 acetylation under in vitro Treg induction conditions with TGF-β and all-trans retinoic acid. Bone marrow (BM) + MCT1 KO vs WT T cells infused into fully MHC-mismatched hosts resulted in decreased aGVHD lethality (p < 0.0001). On d14, lower donor MCT1 KO T cell numbers with attenuated cytotoxin content were seen in non-lymphoid organs including liver, small intestines, and colon. Splenic, liver, and small intestine Tregs and mitochondrial respiration in T cells each were increased. Since GVHD can provide a beneficial graft-vs-tumor (GVT) effect by responses to alloantigens present on tumor cells, host strain A20-luciferase+ lymphoma cells clearance by MCT1 KO vs WT donor T cells was quantified and found equivalent, indicating GVT was not eliminated. These findings highlight the importance of monocarboxylate metabolism in alloreactive T cells and suggest that MCT1 inhibitory drugs already in clinic may reduce GVHD and retain GVT. Funding Sources Supported by ASH Graduate Hematology Award; NIAID P01 AI056299-20 Topic Categories Transplantation Immunology (TRAN)