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

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 b...

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Veröffentlicht in:Cell reports (Cambridge) 2019-08, Vol.28 (7), p.1879-1893.e7
Hauptverfasser: Chakraborty, Paramita, Vaena, Silvia G., Thyagarajan, Krishnamurthy, Chatterjee, Shilpak, Al-Khami, Amir, Selvam, Shanmugam Panneer, Nguyen, Hung, Kang, Inhong, Wyatt, Megan W., Baliga, Uday, Hedley, Zachariah, Ngang, Rose N., Guo, Beichu, Beeson, Gyda C., Husain, Shahid, Paulos, Chrystal M., Beeson, Craig C., Zilliox, Michael J., Hill, Elizabeth G., Mehrotra, Meenal, Yu, Xue-Zhong, Ogretmen, Besim, Mehrotra, Shikhar
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Sprache:eng
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Zusammenfassung: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. [Display omitted] •S1PR-independent intrinsic S1P signaling activates PPARγ to skew the Treg/Th17 balance•S1P-PPARγ activation inversely correlates with lipolysis and regulates Tcm phenotype•Inhibiting SphK1/S1P/PPARγ signaling improves T cell-mediated tumor control Chakraborty et al. define the role for SphK1/S1P signaling via engaging lipid transcription factor PPARγ to attenuate lipolysis and spare respiratory capacity in T cells. Genetic ablation or pharmacological inhibition of SphK1 expression limits intrinsic S1P levels and improves T cell-mediated anti-tumor immunotherapeutic control.
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2019.07.044