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Series GSE269182 Query DataSets for GSE269182
Status Public on Jun 26, 2024
Title CCR1 drives immunosuppressive properties of tumor associated macrophages in pancreatic cancer
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Immunotherapy approaches have been ineffective in pancreatic ductal adenocarcinoma (PDA), pointing to the need for additional avenues to target in the pancreatic cancer microenvironment. We previously discovered that tumor educated bone marrow derived macrophages express high levels of C-C Motif Chemokine Receptor 1 (CCR1). By single-cell RNA sequencing, we found CCR1 to be expressed predominantly by tumor associated macrophages (TAMs) and granulocytes in both human and mouse PDA. Thus, we sought to investigate the functional role of CCR1 in pancreatic cancer. Using KC; Ccr1-/- mice (Ptf1a-Cre; LSL-KrasG12D; Ccr1-/-), we determined that CCR1 is dispensable during pancreatic cancer initiation, although we observed increased CD8 T cell infiltration in KC; Ccr1-/- pancreata. Using syngeneic orthotopic PDA mouse models we discovered that CCR1 ablation in Ccr1-/- mice or pharmaceutical inhibition of CCR1 both resulted in reduced tumor growth. Further, CCR1 ablation prolonged the overall survival of KPC mice. Through mass cytometry (CyTOF) and co-immunofluorescence staining we showed CCR1 ablation elevated CD8 T cell cytotoxic activity in the orthotopic PDA model. Mechanistically we found TAMs lacking CCR1 expressed less Arginase 1 and CD206 -both immunosuppressive markers of macrophages- compared to wild type TAMs. Further, targeting both CCR1 and Arginase 1 synergized with immune checkpoint blockade anti-PD-L1 to enhance antitumor efficacy in orthotopic model of PDA. Together, our data is consistent with the notion that tumor associated macrophages lacking CCR1 expression are less immunosuppressive, consequently allowing increased CD8 T cell mediated anti-tumor immunity. Targeting CCR1 in combination with immune checkpoint blockade improves antitumor efficacy in pancreatic cancer.
 
Overall design We used KC;Ccr1-/- (Ptf1a-Cre;LSL-KrasG12D;Ccr1-/-) to determine the requirement of CCR1 during pancreatic cancer initiation and progression.
 
Contributor(s) Zhang Y, Pasca di Magliano M
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Submission date Jun 05, 2024
Last update date Jun 27, 2024
Contact name Marina Pasca di Magliano
E-mail(s) marinapa@umich.edu
Organization name University of Michigan Medical School
Street address 1500 E Medical Center Dr
City Ann Arbor
State/province MI
ZIP/Postal code 48103
Country USA
 
Platforms (1)
GPL24247 Illumina NovaSeq 6000 (Mus musculus)
Samples (2)
GSM8307724 KC PanIN
GSM8307725 KC_CCR1 KO PanIN
Relations
BioProject PRJNA1120471

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Supplementary file Size Download File type/resource
GSE269182_RAW.tar 129.8 Mb (http)(custom) TAR (of H5)
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Raw data are available in SRA

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