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| Status |
Public on Jul 01, 2020 |
| Title |
Endogenous glucocorticoid signaling regulates effector differentiation and development of dysfunction in CD8+ T cells in the tumor microenvironment |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Identifying signals in the tumor microenvironment (TME) that shape CD8+ T cell phenotype can inform novel therapeutic approaches for cancer. Here, we identified a gradient of increasing glucocorticoid receptor (GR) expression and signaling from naive to dysfunctional CD8+ tumor-infiltrating lymphocytes (TILs). Conditional deletion of the GR in CD8+ TILs resulted in improved effector differentiation, reduced TCF-1 expression, and failure to develop dysfunctional phenotype, culminating in tumor growth inhibition. GR signaling transactivated the expression of multiple checkpoint receptors and promoted the induction of several dysfunction-associated genes upon T cell activation. In the TME, monocyte/macrophages produced glucocorticoids and genetic ablation of steroidogenesis in these cells as well localized pharmacologic inhibition of glucocorticoid biosynthesis dramatically improved tumor growth control. Active glucocorticoid signaling further associated with failure to respond to checkpoint blockade in both pre-clinical models and melanoma patients, highlighting the clinical relevance of targeting endogenous steroid signaling to enhance anti-tumor T cell responses.
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| Overall design |
wild type (E8i-Cre-Nr3c1fl/fl) or E8i-Cre+Nr3c1fl/fl CD8+ T cells activated in the presence or absence of glucocorticoid (GC;dexamethasone) for 72hrs and wild type CD8+ T cell 9 days activated in the presence or absence of glucocorticoid (GC;dexamethasone), IL27 or both
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| Contributor(s) |
Carrizosa Anderson A, Madi A, Acharya N |
| Citation(s) |
32937153 |
| |
| Submission date |
Jun 30, 2020 |
| Last update date |
Sep 30, 2020 |
| Contact name |
Asaf Madi |
| E-mail(s) |
[email protected]
|
| Organization name |
BWH
|
| Department |
Neurology
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| Lab |
Ana Carrizosa Anderson
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| Street address |
60 Fenwood Road, BTM 10016F
|
| City |
Boston |
| State/province |
MA |
| ZIP/Postal code |
02115 |
| Country |
USA |
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| Platforms (1) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
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| Samples (24)
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| Relations |
| BioProject |
PRJNA643231 |
| SRA |
SRP269378 |
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