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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Jan 13, 2020 |
| Title |
Regulatory T Cell depletion causes compensatory immune suppression and accelerated pancreatic carcinogenesis |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
In human patients and in mouse models, immunosuppressive regulatory T cells(Tregs)accumulate in Pancreatic Intraepithelial Neoplasia (PanIN), the precursor lesions to pancreatic cancer. Tregs are considered a potential therapeutic target with the goal to reverse immunosuppression in a number of malignancies, including pancreatic cancer. Here, using a genetically engineered mouse that allows at will depletion of Tregs during pancreatic carcinogenesis, we determined that Treg depletion failed to relieve immunosuppression. Contradicting the current paradigm, depletion of Tregs led to accelerated tumorprogression. We demonstratedthat Treg depletion resultsin changes in the fibroblast population, exemplified by loss of Smooth Muscle Actinexpression and an increase the myeloid recruiting chemokines Ccl3, Ccl6, and Ccl8. Treg depletion further resulted ina compensatoryinflux of suppressive myeloid cells, thereby preventing an anti-tumor immune response. Mechanistically, we show that themyeloid recruitment was driven through the CCR1 axis, with the receptor expressed on tumor associated myeloid cells and several ligands up-regulated in epithelial cells and fibroblasts upon Treg depletion. Finally,blockade of CCR1 signalingcombined with Treg-depletionsuccessfully inhibitedtumorigenesis, uncovering the immune-suppressive myeloid CCR1 axis as a potential therapeutic targetin pancreatic cancer.
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| Overall design |
Single cell RNA sequencing of whole iKras-ON orthotopic tumor (2 replicates) and early 3 week iKras-ON lesions
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| Contributor(s) |
Zhang Y, Sirihorachai V, Donahue K |
| Citation(s) |
31911451 |
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| Submission date |
Nov 18, 2019 |
| Last update date |
Jan 11, 2022 |
| Contact name |
Marina Pasca Di Magliano |
| Organization name |
University of Michigan
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| Street address |
1500 E Medical Center Dr.
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| City |
Ann Arbor |
| State/province |
MI |
| ZIP/Postal code |
48103 |
| Country |
USA |
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| Platforms (1) |
| GPL21103 |
Illumina HiSeq 4000 (Mus musculus) |
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| Samples (3) |
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| Relations |
| BioProject |
PRJNA590272 |
| SRA |
SRP301811 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE140628_Mouse_On_Merge_Fil.RData.gz |
346.6 Mb |
(ftp)(http) |
RDATA |
| GSE140628_RAW.tar |
366.1 Mb |
(http)(custom) |
TAR (of H5, MTX, RDATA, TSV) |
SRA Run Selector |
| Processed data provided as supplementary file |
| Raw data are available in SRA |
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