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| Status |
Public on Apr 08, 2022 |
| Title |
Carbon-monoxide Induced PERK Regulated Autophagy Reprograms Anti-Tumor T Cells with Robust Immunometabolic Phenotype |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Mitochondria and Endoplasmic reticulum (ER) share structural and functional networks and activates well-orchestrated signaling processes to shape a cell’s fate and function. While persistent ER stress (ERS) response leads to mitochondrial collapse, moderate ERS condition promotes mitochondrial function. Strategies to boost anti-tumor T cell function by targeting ERMitochondria crosstalk have not been exploited yet. Thus, we used carbon monoxide (CO), a short-lived gaseous molecule, to test if engaging moderate ERS conditions can improve T cells mitochondrial function and anti-tumor function. Using melanoma antigen specific T cells, we identify that CO induced transient activation of ERS sensor ‘protein kinase R-like endoplasmic reticulum kinase (PERK)’ dramatically increase anti-tumor T cell function. Furthermore, COinduced PERK activation temporarily halts protein translation and induces protective autophagy (that includes mitophagy). To get further insight, we used LC3-GFP to differentiate between the cells that prepare themselves to undergo active autophagy (LC3-GFPpos) and those that fail to enter into the process (LC3-GFPneg). We found that LC3-GFPpos T cells show robust anti-tumor potential whereas, LC3-GFPneg cells show T regulatory-like phenotype, harbor dysfunctional mitochondria, and accumulate abnormal metabolite content. These anomalous ratios of metabolites render the cells with a hypermethylated state and distinct epigenetic profile limiting their anti-tumor activity. Overall, the study highlights that ERS activated autophagy pathways modify mitochondrial function and epigenetically reprogram the T cells towards a superior antitumor phenotype to achieve robust tumor control.
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| Overall design |
Examination of mRNA profiles in T cells using RNA-seq.
Examination of chromatin accessibility in T cells using ATAC-seq.
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| Contributor(s) |
Chakraborty P, Parikh R, Gangaraju V, Mehrotra S |
| Citation missing |
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| |
| Submission date |
Feb 27, 2022 |
| Last update date |
Apr 08, 2022 |
| Contact name |
Vamsi Gangaraju |
| Organization name |
Medical University of South Carolina
|
| Street address |
173 Ashley Ave
|
| City |
Charleston |
| ZIP/Postal code |
29466 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (16)
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| Relations |
| BioProject |
PRJNA810845 |
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