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 proli... More
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.
