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Series GSE140628 Query DataSets for GSE140628
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
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.
Overall design Single cell RNA sequencing of whole iKras-ON orthotopic tumor (2 replicates) and early 3 week iKras-ON lesions
Contributor(s) Zhang Y, Sirihorachai V, Donahue K
Citation(s) 31911451
Submission date Nov 18, 2019
Last update date Jan 11, 2022
Contact name Marina Pasca Di Magliano
Organization name University of Michigan
Street address 1500 E Medical Center Dr.
City Ann Arbor
State/province MI
ZIP/Postal code 48103
Country USA
Platforms (1)
GPL21103 Illumina HiSeq 4000 (Mus musculus)
Samples (3)
GSM4175979 ON1
GSM4175980 ON2
GSM4175981 Run_2788_Mouse: iKras_3w_ON
BioProject PRJNA590272
SRA SRP301811

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SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

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 SelectorHelp
Processed data provided as supplementary file
Raw data are available in SRA

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