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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Oct 10, 2018 |
| Title |
Mouse Myeloid panel on G-MDSCs from treated tumors |
| Organism |
Mus musculus |
| Experiment type |
Other
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| Summary |
Immune checkpoint inhibition (ICI) has revolutionized treatment in cancers that are naturally immunogenic by enabling infiltration of T cells into the tumor microenvironment (TME) and promoting cytotoxic signaling pathways. Tumors possessing complex immunosuppressive TME’s such as breast and pancreatic cancers present unique therapeutic obstacles as response rates to ICI remain low. Such tumors often recruit myeloid-derived suppressor cells (MDSCs) whose functioning prohibits both T-cell activation and infiltration. We attempted to sensitize these tumors to ICI using epigenetic modulation to target MDSC trafficking and function to foster a less immunosuppressive TME. We showed that combining a histone deacetylase inhibitor, entinostat (ENT), with anti–PD-1, anti–CTLA-4, [A1] [A2] or both, significantly improved tumor-free survival in both the HER2/neu transgenic breast cancer and the Panc02 metastatic pancreatic cancer mouse models. Using flow cytometry, gene expression profiling, and ex vivo functional assays, we characterized populations of tumor-infiltrating lymphocytes (TILs) and MDSCs, as well as their functional capabilities. We showed that addition of ENT to checkpoint inhibition led to significantly decreased suppression by granulocytic-MDSCs in the TME of both tumor types. We also demonstrated an increase in activated granzyme-B–producing CD8+ T effector cells in mice treated with combination therapy. Gene expression profiling of both MDSCs and TILs identified significant changes in immune-related pathways. In summary, addition of ENT to ICI significantly altered infiltration and function of innate immune cells, allowing for a more robust adaptive immune response. These findings provide a rationale for combination therapy in patients with immune-resistant tumors, including breast and pancreatic cancers.
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| Overall design |
To identify possible mechanisms for their impaired function, we utilized NanoString transcript profiling to evaluate broad changes in the transcriptome of isolated G-MDSCs induced by treatment.
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| Contributor(s) |
Roussos Torres ET, Christmas BJ, Hopkins AC, Rafie CI, Jaffee EM |
| Citation(s) |
30341213 |
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| Submission date |
Oct 09, 2018 |
| Last update date |
Jan 09, 2019 |
| Contact name |
Evanthia Theodosiou Roussos Torres |
| Organization name |
Johns Hopkins University
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| Department |
Oncology
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| Lab |
Jaffee Lab
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| Street address |
1650 Orleans Street, CRB1 4M
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| City |
Baltimore |
| State/province |
Maryland |
| ZIP/Postal code |
21287 |
| Country |
USA |
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| Platforms (1) |
| GPL25266 |
NanoString Mouse nCounter Myeloid Innate Immunity Panel NS_Mm_Myeloid_V2.0 |
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| Samples (22)
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| Relations |
| BioProject |
PRJNA495380 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE121030_MyeloidNormalizedDataRaw.csv.gz |
47.0 Kb |
(ftp)(http) |
CSV |
| GSE121030_RAW.tar |
190.0 Kb |
(http)(custom) |
TAR (of RCC) |
| Processed data included within Sample table |
| Processed data are available on Series record |
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