Pro-Survival Lipid Sphingosine-1-Phosphate Metabolically Programs T Cells to Limit Anti-tumor Activity
| Autor: | Besim Ogretmen, Shikhar Mehrotra, Rose N. Ngang, Hung Nguyen, Gyda C. Beeson, Paramita Chakraborty, Silvia G. Vaena, Uday K Baliga, Beichu Guo, Meenal Mehrotra, Shahid Husain, Michael J. Zilliox, Krishnamurthy Thyagarajan, Shanmugam Panneer Selvam, In-Hong Kang, Zachariah Hedley, Chrystal M. Paulos, Amir A. Al-Khami, Craig Beeson, Xue-Zhong Yu, Elizabeth G. Hill, Megan W. Wyatt, Shilpak Chatterjee |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Sphingosine-1-phosphate receptor T cell Lymphocyte T-Lymphocytes Melanoma Experimental General Biochemistry Genetics and Molecular Biology Article Oxidative Phosphorylation 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Sphingosine medicine Animals Sphingosine-1-phosphate lcsh:QH301-705.5 S1PR1 Mice Knockout biology Lipid signaling Cellular Reprogramming 3. Good health Cell biology Gene Expression Regulation Neoplastic Mice Inbred C57BL PPAR gamma Phosphotransferases (Alcohol Group Acceptor) Receptors Lysosphingolipid 030104 developmental biology medicine.anatomical_structure lcsh:Biology (General) chemistry Sphingosine kinase 1 biology.protein lipids (amino acids peptides and proteins) Female Lysophospholipids 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Cell reports Cell Reports, Vol 28, Iss 7, Pp 1879-1893.e7 (2019) |
| ISSN: | 2211-1247 |
| Popis: | SUMMARY 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. Graphical Abstract In Brief 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. |
| Databáze: | OpenAIRE |
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