Journal
CELL REPORTS
Volume 28, Issue 7, Pages 1879-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2019.07.044
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Funding
- NIH, United States [R21CA137725, R01CA138930, P01CA154778, R01CA173687, R01CA214461, R01DE016572, PO1 CA203628]
- SmartState Endowment in Lipidomics and Drug Discovery
- American Association of Immunologists, United States, Careers in Immunology Fellowship
- Hollings Cancer Center Shared Resources at MUSC [P30 CA138313]
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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 PPAR gamma (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.
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