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1.
Cell Rep ; 28(7): 1879-1893.e7, 2019 08 13.
Article in English | MEDLINE | ID: mdl-31412253

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.


Subject(s)
Cellular Reprogramming , Gene Expression Regulation, Neoplastic , Lysophospholipids/metabolism , Melanoma, Experimental/pathology , PPAR gamma/physiology , Phosphotransferases (Alcohol Group Acceptor)/physiology , Sphingosine/analogs & derivatives , T-Lymphocytes/immunology , Animals , Female , Male , Melanoma, Experimental/immunology , Melanoma, Experimental/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Oxidative Phosphorylation , Receptors, Lysosphingolipid/metabolism , Signal Transduction , Sphingosine/metabolism , T-Lymphocytes/metabolism
2.
Cell Metab ; 27(1): 85-100.e8, 2018 01 09.
Article in English | MEDLINE | ID: mdl-29129787

ABSTRACT

Heightened effector function and prolonged persistence, the key attributes of Th1 and Th17 cells, respectively, are key features of potent anti-tumor T cells. Here, we established ex vivo culture conditions to generate hybrid Th1/17 cells, which persisted long-term in vivo while maintaining their effector function. Using transcriptomics and metabolic profiling approaches, we showed that the enhanced anti-tumor property of Th1/17 cells was dependent on the increased NAD+-dependent activity of the histone deacetylase Sirt1. Pharmacological or genetic inhibition of Sirt1 activity impaired the anti-tumor potential of Th1/17 cells. Importantly, T cells with reduced surface expression of the NADase CD38 exhibited intrinsically higher NAD+, enhanced oxidative phosphorylation, higher glutaminolysis, and altered mitochondrial dynamics that vastly improved tumor control. Lastly, blocking CD38 expression improved tumor control even when using Th0 anti-tumor T cells. Thus, strategies targeting the CD38-NAD+ axis could increase the efficacy of anti-tumor adoptive T cell therapy.


Subject(s)
ADP-ribosyl Cyclase 1/metabolism , Immunotherapy , NAD/metabolism , Neoplasms/immunology , Neoplasms/therapy , T-Lymphocytes/immunology , Animals , Forkhead Box Protein O1/metabolism , Glutamine/metabolism , Mice, Inbred C57BL , Neoplasms/metabolism , Sirtuin 1/metabolism , Th1 Cells/immunology , Th17 Cells/immunology
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