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Cell Rep. 2019 Aug 13;28(7):1879-1893.e7. doi: 10.1016/j.celrep.2019.07.044.

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

Author information

1
Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
2
Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
3
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA.
4
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
5
Department of Pharmaceutical and Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, USA.
6
Department of Ophthalmology, Medical University of South Carolina, Charleston, SC 29425, USA.
7
Department of Public Health Sciences, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA.
8
Department of Public Health, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
9
Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. Electronic address: ogretmen@musc.edu.
10
Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. Electronic address: mehrotr@musc.edu.

Abstract

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.

KEYWORDS:

Foxo1; PPARγ; S1P; SphK1; T cell; Tcm; immunotherapy; lipid signaling; melanoma

PMID:
31412253
DOI:
10.1016/j.celrep.2019.07.044
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