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| Status |
Public on Feb 13, 2024 |
| Title |
A ketogenic diet can revert acquired resistance to immunotherapy in prostate cancer through β-hydroxybutyrate-mediated inhibition of histone deacetylases |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
Other
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| Summary |
Prostate cancer is the second leading cause of cancer deaths in men in the US. In the past decade, immune checkpoint blockade (ICB) drugs targeting programmed death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) have revolutionized the field of cancer therapeutics, but the objective response rate in prostate cancers is in the low single digits. A major complicating issue is that immunotherapies can have significant adverse effects, so there is a clinical need for novel combinatorial strategies that do not involve additional or compounding adverse effects. We developed a model system of advanced prostate cancer that has acquired resistance to ICB therapy. The PD-1 resistant sublines showed strong downregulation of the mouse major histocompatibility complex (MHC-I), which was reversed by treating cells with either the pan-histone deacetylase (HDAC) inhibitor Vorinostat or β-hydroxybutyrate. When mice bearing these ICB resistant tumor are treated with either Vorinostat, with a cyclical ketogenic diet (CKD), or with a 1,3-butanediol diet (BD), tumors are resensitized to ICB therapy. We analyzed changes in the tumor immune microenvironment and showed that this effect is driven by a shift in monocyte differentiation, changing from M2 polarized immunosuppressive macrophages into iNOS+ dendritic cells instead. This differentiation is dependent on an ICB-induced increase in CD40L+ CD8+ T-cells in the tumor immune microenvironment. Our results indicate a novel mechanism in which a ketogenic diet can be used to increase therapeutic efficacy of ICB therapy.
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| Overall design |
Samples consist of single cell suspensions, derived from 3 different tumors per treatment group (standard diet (SD), butanediol diet (BD), immune checkpoint blockade (ICB), and BD + ICB.
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| Contributor(s) |
Murphy S, Rahmy S, Gan D, Lu X |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| |
| Submission date |
Jun 21, 2022 |
| Last update date |
Feb 14, 2024 |
| Contact name |
Xin Lu |
| E-mail(s) |
xlu@nd.edu
|
| Phone |
574-631-6592
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| Organization name |
University of Notre Dame
|
| Department |
Biological Sciences
|
| Lab |
Lu lab
|
| Street address |
109 Galvin Life Science Center
|
| City |
Notre Dame |
| State/province |
IN |
| ZIP/Postal code |
46556 |
| Country |
USA |
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| Platforms (1) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA851379 |
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