 |
 |
GEO help: Mouse over screen elements for information. |
|
| Status |
Public on Jul 31, 2019 |
| Title |
Pro-survival Lipid Sphingosine-1-Phosphate Metabolically Reprograms T cell to Limit its Anti-Tumor Activity |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Sphingosine 1-phosphate (S1P), a pro-tumor survival bioactive lysophospholipid, generated by sphingosine kinase 1 (SphK1), regulates lymphocyte egress into circulation via transducing S1P receptor 1 (S1PR1) signalling, and also plays a role in the differentiation of regulatory T cells and T helper-17 cells. However, the mechanisms by which receptor-independent SphK1/S1P signallng regulates anti-tumor T cell activity remain unknown. Using melanoma antigen gp100 reactive T cells deficient in Sphk1, we found that Pmel-Sphk1-/- T cells maintained central memory phenotype, showed higher mitochondrial respiration, and exhibited resistance to TGF-β mediated suppression. Mechanistically, we discovered a direct correlation between SphK1 generated intracellular S1P and PPARγ (peroxisome proliferator-activated receptor gamma) activity, which in turn regulate lipolysis in T cells. Genetic, molecular or pharmacologic inhibition of SphK1 or PPARγ improved metabolic fitness and anti-tumor activity of T cells. Further, inhibition of SphK1 and PD1 together led to long-term control of melanoma. Overall, these data highlight the clinical potential of targeting SphK1/S1P for improved anti-cancer adoptive T cell immunotherapy.
|
| |
|
| Overall design |
Duplicate samples were analyzed from the WT and Sphingosine Kinase deficient mouse. The splenic T cells were activated wih cognate antigen (gp100) for three days before the RNA was prepared and RNA seq. performed.
|
| |
|
| Contributor(s) |
Mehrotra S, Zilliox M |
| Citation(s) |
31412253 |
| |
| Submission date |
Apr 08, 2019 |
| Last update date |
Dec 10, 2019 |
| Contact name |
Michael J Zilliox |
| E-mail(s) |
mizilliox@luc.edu
|
| Organization name |
Loyola University Chicago
|
| Department |
Ophthalmology
|
| Street address |
2160 S. First Ave
|
| City |
Maywood |
| State/province |
IL |
| ZIP/Postal code |
60559 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
|
| Samples (4)
|
|
| Relations |
| BioProject |
PRJNA531482 |
| SRA |
SRP191448 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE129489_SphK1_KO_vs_control.xlsx |
880.1 Kb |
(ftp)(http) |
XLSX |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
|
|
|
|
 |
Less...
More...