Pro-Survival Lipid Sphingosine-1-Phosphate Metabolically Programs T Cells to Limit Anti-tumor Activity

Cell Rep. 2019 Aug 13;28(7):1879-1893.e7. doi: 10.1016/j.celrep.2019.07.044.


Sphingosine 1-phosphate (S1P), a bioactive lysophospholipid generated by sphingosine kinase 1 (SphK1), regulates lymphocyte egress into circulation via S1P receptor 1 (S1PR1) signaling, and it controls the differentiation of regulatory T cells (Tregs) and T helper-17 cells. However, the mechanisms by which receptor-independent SphK1-mediated intracellular S1P levels modulate T cell functionality remains unknown. We show here that SphK1-deficient T cells maintain central memory phenotype and exhibit higher mitochondrial respiration and reduced differentiation to Tregs. Mechanistically, we discovered a direct correlation between SphK1-generated S1P and lipid transcription factor PPARγ (peroxisome proliferator-activated receptor gamma) activity, which in turn regulates lipolysis in T cells. Genetic and pharmacologic inhibition of SphK1 improved metabolic fitness and anti-tumor activity of T cells against murine melanoma. Further, inhibition of SphK1 and PD1 together led to improved control of melanoma. Overall, these data highlight the clinical potential of limiting SphK1/S1P signaling for enhancing anti-tumor-adoptive T cell therapy.

Keywords: Foxo1; PPARγ; S1P; SphK1; T cell; Tcm; immunotherapy; lipid signaling; melanoma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cellular Reprogramming*
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Lysophospholipids / metabolism*
  • Male
  • Melanoma, Experimental / immunology
  • Melanoma, Experimental / metabolism
  • Melanoma, Experimental / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oxidative Phosphorylation
  • PPAR gamma / physiology*
  • Phosphotransferases (Alcohol Group Acceptor) / physiology*
  • Receptors, Lysosphingolipid / metabolism
  • Signal Transduction
  • Sphingosine / analogs & derivatives*
  • Sphingosine / metabolism
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism


  • Lysophospholipids
  • PPAR gamma
  • Pparg protein, mouse
  • Receptors, Lysosphingolipid
  • sphingosine 1-phosphate
  • Phosphotransferases (Alcohol Group Acceptor)
  • Sphk1 protein, mouse
  • Sphingosine