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| Status |
Public on Aug 10, 2020 |
| Title |
CD28 Co-stimulation Drives Tumor-Infiltrating T Cell Glycolysis to Promote Inflammation |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Metabolic reprogramming dictates the fate and function of stimulated T cells, yet these pathways can be suppressed in T cells subjected to unique microenvironments, such as in a tumor. We previously showed that glycolytic and mitochondrial adaptations directly contribute to reduced effector functions of Renal Cell Carcinoma (RCC) CD8 tumor infiltrating lymphocytes (TIL). Here we define the role of these metabolic pathways in the activation and effector functions of RCC CD8 TIL. CD28 co-stimulation plays a key role to augment T cell activation and metabolism and is antagonized by inhibitory and checkpoint immunotherapy receptors CTLA4 and PD-1. While RCC CD8 TIL activated poorly when stimulated through the T cell receptor alone, addition of CD28 co-stimulation greatly enhanced activation, function, and proliferation. CD28 co-stimulation reprogrammed RCC CD8 TIL metabolism with increased glycolysis and mitochondrial oxidative metabolism, in part through upregulation of GLUT3. Mitochondria also became more fused, with higher membrane potential and overall mass. These phenotypes were dependent on glucose metabolism, as the glycolytic inhibitor 2-deoxyglucose both prevented changes to mitochondria and suppressed RCC CD8 TIL activation and function. These data show that CD28 co-stimulation can restore RCC CD8 TIL metabolism and function through rescue of T cell glycolysis that supports mitochondrial mass and activity.
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| Overall design |
CD8+ T cells were isolated from patient peripheral blood and ccRCC tumor. Then the CD8+ T cells were treated with IL7, anti-CD3, anti-CD3/CD28 and anti-CD3/CD28/IL2 for 5 days and subject to single cell RNA sequencing. Bulk RNA sequencing done on sorted peripheral CD8 T cell and ccRCC TIL CD8 T cells without treatment.
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| Contributor(s) |
Beckermann KE, Young K, Ye X, Hongo R, Rathmell K, Rathmell JC |
| Citation(s) |
32814710 |
| |
| Submission date |
Jun 02, 2020 |
| Last update date |
Sep 08, 2020 |
| Contact name |
John Karijolich |
| E-mail(s) |
john.karijolich@vumc.org
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| Organization name |
Vanderbilt University Medical Center
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| Department |
PMI
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| Lab |
John Karijolich Lab
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| Street address |
1211 Medical Center Drive
|
| City |
Nashville |
| State/province |
TN |
| ZIP/Postal code |
37232 |
| Country |
USA |
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| Platforms (1) |
| GPL20301 |
Illumina HiSeq 4000 (Homo sapiens) |
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| Samples (18)
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| Relations |
| BioProject |
PRJNA636802 |
| SRA |
SRP265649 |
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