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| Status |
Public on Oct 18, 2018 |
| Title |
IRE1α-XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Tumors evade immune control by creating hostile microenvironments that perturb T cell metabolism and effector function. However, it remains unclear how intratumoral T cells integrate and interpret metabolic stress signals. Here we report that ovarian cancer (OvCa), an aggressive malignancy refractory to standard treatments and current immunotherapies, induces Endoplasmic Reticulum (ER) stress and activation of the IRE1α-XBP1 arm of the Unfolded Protein Response (UPR)10,11 in T cells to control their mitochondrial respiration and anti-tumor function. XBP1 upregulation in T cells isolated from human OvCa specimens was associated with decreased intratumoral T cell infiltration and reduced IFNG mRNA expression. Malignant ascites fluid obtained from OvCa patients inhibited glucose uptake and caused N-linked protein glycosylation defects in T cells, leading to IRE1α/XBP1-driven suppression of mitochondrial activity and IFN- production. Mechanistically, XBP1 induction limited the influx of glutamine necessary to sustain T cell mitochondrial respiration under glucose-deprived conditions by regulating the abundance of glutamine carriers. Restoring N-linked protein glycosylation, abrogating IRE1α-XBP1 activation or enforcing expression of glutamine transporters enhanced mitochondrial respiration in human T cells exposed to OvCa ascites. XBP1-deficient T cells in the metastatic OvCa milieu exhibited global transcriptional reprogramming and improved effector capacity. Accordingly, OvCa-bearing mice lacking XBP1 selectively in T cells demonstrated superior anti-tumor immunity, delayed malignant progression and increased overall survival. Therefore, controlling ER stress or targeting IRE1α-XBP1 signaling may help restore T cell metabolic fitness and anti-tumor capacity in cancer hosts.
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| Overall design |
RNA-seq in XBP1 WT and KO CD4 tumor infiltrating Tcells
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| Contributor(s) |
Cubillos-Ruiz JR, Song M |
| Citation(s) |
30305738 |
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| Submission date |
Aug 10, 2018 |
| Last update date |
Mar 19, 2019 |
| Contact name |
Priyankara J Wickramasinghe |
| E-mail(s) |
priyaw@wistar.org
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| Phone |
2154956837
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| Organization name |
The Wistar Institute
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| Department |
Bioinformatics
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| Lab |
Genomics
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| Street address |
3601 Spruce Street
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| City |
Philadelphia |
| State/province |
PA |
| ZIP/Postal code |
19104 |
| Country |
USA |
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| Platforms (1) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
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| Samples (8)
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| Relations |
| BioProject |
PRJNA485534 |
| SRA |
SRP157113 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE118430_XBP1_CD4_gene_counts.txt.gz |
434.9 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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