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
Date
08/15/2019Pubmed ID
31412253Pubmed Central ID
PMC6889821DOI
10.1016/j.celrep.2019.07.044Scopus ID
2-s2.0-85071280128 (requires institutional sign-in at Scopus site) 67 CitationsAbstract
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.
Author List
Chakraborty P, Vaena SG, Thyagarajan K, Chatterjee S, Al-Khami A, Selvam SP, Nguyen H, Kang I, Wyatt MW, Baliga U, Hedley Z, Ngang RN, Guo B, Beeson GC, Husain S, Paulos CM, Beeson CC, Zilliox MJ, Hill EG, Mehrotra M, Yu XZ, Ogretmen B, Mehrotra SAuthor
Xue-Zhong Yu MD Professor in the Microbiology and Immunology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCellular Reprogramming
Female
Gene Expression Regulation, Neoplastic
Lysophospholipids
Male
Melanoma, Experimental
Mice
Mice, Inbred C57BL
Mice, Knockout
Oxidative Phosphorylation
PPAR gamma
Phosphotransferases (Alcohol Group Acceptor)
Receptors, Lysosphingolipid
Signal Transduction
Sphingosine
T-Lymphocytes
