Sphingolipid metabolism in T cell responses after allogeneic hematopoietic cell transplantation

Abstract

Allogeneic hematopoietic cell transplantation (allo-HCT) is an effective immunotherapy against hematopoietic malignancies. The infused donor lymphocytes attack malignant cells and normal tissues, termed a graft-verse-leukemia (GVL) effect and graft-verse-host (GVH) response or disease (GVHD), respectively. Although engineering techniques toward donor graft selection have made HCT more specific and effective, primary tumor relapse and GVHD are still major concerns post allo-HCT. High-dose systemic steroids remain to be the first line of GVHD treatment, which may lead to steroid-refractory GVHD with a dismal outcome. Therefore, identifying novel therapeutic strategies that prevent GVHD while preserving GVL activity is highly warranted. Sphingolipid metabolism and metabolites play pivotal roles in regulating T-cell homeostasis and biological functions. In this review, we summarized the recent research progress in this evolving field of sphingolipids with a focus on alloreactive T-cell responses in the context of allo-HCT. We discussed how sphingolipid metabolism regulates T-cell mediated GVH and GVL responses in allo-HCT and presented the rationale and means to target sphingolipid metabolism for the control of GVHD and leukemia relapse.

The integration of quantitative metabolic and proteomic analysis uncovers an augmentation of the sphingolipid biosynthesis pathway during T-cell differentiation

“…Speci cally, we observed almost 2-fold increase in CerS2 and Cers5 expression in activated Th cells, which synthesize C22-/C24-/C26-Cer or C14-/C16-Cer, respectively 21,22 . In contrast, only slight changes were observed in the expression of CerS4 and CerS6, which produce C18-/C20-Cer or C14-/C16-Cer, respectively 21,22 . Consistent with the upregulation of CerS2, the proportion of Cer (d18:1/24:0) in ceramide lipids was signi cantly increased following TCR stimulation (from 8.19% in naïve CD4 + T cells to 26.9% in Th0 cells, 26.2% in Th1 cells, 21.4% in Th2 cells, 17.5% in Th17 cells, and 16.8% in iTreg cells).…”

“…Our proteomic analysis revealed that changes in the protein expression of CerS family upon TCR stimulation. Speci cally, we observed almost 2-fold increase in CerS2 and Cers5 expression in activated Th cells, which synthesize C22-/C24-/C26-Cer or C14-/C16-Cer, respectively 21,22 . In contrast, only slight changes were observed in the expression of CerS4 and CerS6, which produce C18-/C20-Cer or C14-/C16-Cer, respectively 21,22 .…”

Interplay of Sphingolipid Metabolism in Predicting Prognosis of GBM Patients: Towards Precision Immunotherapy

“…Additionally, sphingolipids exert significant regulatory influence as major lipid components of the myelin sheath surrounding nerve axons. Consequently, a thorough exploration of sphingolipid metabolic processes holds the potential to inform future therapeutic strategies for glioblastoma 32 , 33 . Leveraging comprehensive transcriptome sequencing data, our study reinforces the notion that unraveling the biological significance of sphingolipid metabolic pathways could serve as a compelling driving force in the current therapeutic landscape of glioblastoma.…”

Signaling controversy and future therapeutical perspectives of targeting sphingolipid network in cancer immune editing and resistance to tumor necrosis factor-α immunotherapy

“…The changes were associated with activation of mitochondrial metabolism [ 388 , 389 ]. Recent findings indicate a key role of sphingolipids in the regulation of cancer metabolism and anticancer immune responses [ 20 , 390 ]. Dramatic changes in sphingolipid composition and processing were reported in cancer tissues [ 391 ].…”