Metabolic Reprogramming—A New Era How to Prevent and Treat Graft Versus Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation Has Begun

Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) is the solitary therapeutic therapy for many types of hematological cancers. The benefits of this procedure are challenged by graft vs. host disease (GVHD), causing significant morbidity and mortality. Recent advances in the metabolomics field have revolutionized our understanding of complex human diseases, clinical diagnostics and allow to trace the de novo biosynthesis of metabolites. There is growing evidence for metabolomics playing a role in different aspects of GVHD, and therefore metabolomic reprogramming presents a novel tool for this disease. Pre-transplant cytokine profiles and metabolic status of allogeneic transplant recipients is shown to be linked with a threat of acute GVHD. Immune reactions underlying the pathophysiology of GVHD involve higher proliferation and migration of immune cells to the target site, requiring shifts in energy supply and demand. Metabolic changes and reduced availability of oxygen result in tissue and cellular hypoxia which is extensive enough to trigger transcriptional and translational changes. T cells, major players in acute GVHD pathophysiology, show increased glucose uptake and glycolytic activity. Effector T (Teff) cells activated during nutrient limiting conditions in vitro or multiplying during GVHD in vivo, depend more on oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO). Dyslipidemia, such as the increase of medium and long chain fatty and polyunsaturated acids in plasma of GVHD patients, has been observed. Sphingolipids associate with inflammatory conditions and cancer. Chronic GVHD (cGVHD) patients show reduced branched-chain amino acids (BCAAs) and increased sulfur-containing metabolites post HSCT. Microbiota-derived metabolites such as aryl hydrocarbon receptor (AhR) ligands, bile acids, plasmalogens and short chain fatty acids vary significantly and affect allogeneic immune responses during acute GVHD. Considering the multitude of possibilities, how altered metabolomics are involved in GVHD biology, multi-timepoints related and multivariable biomarker panels for prognosticating and understanding GVHD are needed. In this review, we will discuss the recent work addressing metabolomics reprogramming to control GVHD in detail.

Invariant natural killer T-cell subsets have diverse graft-versus-host-disease–preventing and antitumor effects

“…Interestingly, iNKT1 cells seemed to downregulate Tcon gene sets involved in oxidative phosphorylation, suggesting the induction of a metabolic switch toward glycolysis, a proinflammatory metabolic state in GVHD. 36,37 Collectively, our data confirm at the transcriptomic level that distinct iNKT sublineages differentially affect Tcon during GVHD and increase our knowledge about mechanisms involved in GVHD prevention by iNKT cells. Finally, differences in iNKT sublineage tissue migration might contribute to the differences in GVHD suppression.…”

Pretransplant Systemic Lipidomic Profiles in Allogeneic Stem Cell Transplant Recipients

“…Our present results suggest that the pretransplant lipidomic profiles differ between allotransplant recipients. Metabolic reprogramming is now suggested as a possible strategy for prophylaxis/treatment of GVHD [ 89 , 90 , 91 , 92 , 93 ], and our results suggest that the effect of such strategies will differ between patients and/or the optimal strategy for targeting metabolic pathways will differ between patients. Our study also suggests that pretransplant lipid levels may be used as biomarkers for the risk of GVHD and/or possibly also for subclassification of patients with regard to the possible and/or optimal use of metabolic targeting.…”

“…All of these three factors are associated with altered levels of various lipid metabolites that are important regulators of fundamental cellular functions, both in various normal cells and malignant cells. Metabolic targeting is now suggested as a possible therapeutic strategy in allotransplant recipients [ 89 , 90 , 91 , 92 , 93 , 106 , 107 ]. Our present study suggests that allotransplant recipients are heterogeneous with regard to their lipidomic profiles and their metabolic regulation, and the effect of metabolic targeting (e.g., nutritional support to increase/normalize the systemic lipid levels) and/or the optimal strategy for optimal targeting may therefore differ between patient subsets.…”

iNKT: A new avenue for CAR-based cancer immunotherapy

“…verified the ability of purified CD4 + iNKT cells to maintain graft-versus-tumor (GvT) effect by constructing two kinds of allogeneic hematopoietic cell transplantation (HCT) models in mice [45] . It has been reported that iNKT1 can down regulate the oxidative phosphorylation of traditional T cells, accelerate the transformation of glycolysis, and cause pro-inflammatory metabolic state, which may lead to the risk of GvHD [ 46 , 47 ]. However, iNKT cells can modulate GvHD through IL-4 production, and iNKT2 and iNKT17 are potential IL-4 producers.…”