Single-cell RNA sequencing reveals the effects of chemotherapy on human pancreatic adenocarcinoma and its tumor microenvironment
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Published:2023-02-13
Issue:1
Volume:14
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Werba GregorORCID, Weissinger Daniel, Kawaler Emily A., Zhao Ende, Kalfakakou DespoinaORCID, Dhara Surajit, Wang Lidong, Lim Heather B., Oh Grace, Jing Xiaohong, Beri Nina, Khanna Lauren, Gonda Tamas, Oberstein PaulORCID, Hajdu Cristina, Loomis Cynthia, Heguy AdrianaORCID, Sherman Mara H.ORCID, Lund Amanda W.ORCID, Welling Theodore H., Dolgalev IgorORCID, Tsirigos AristotelisORCID, Simeone Diane M.ORCID
Abstract
AbstractThe tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) is a complex ecosystem that drives tumor progression; however, in-depth single cell characterization of the PDAC TME and its role in response to therapy is lacking. Here, we perform single-cell RNA sequencing on freshly collected human PDAC samples either before or after chemotherapy. Overall, we find a heterogeneous mixture of basal and classical cancer cell subtypes, along with distinct cancer-associated fibroblast and macrophage subpopulations. Strikingly, classical and basal-like cancer cells exhibit similar transcriptional responses to chemotherapy and do not demonstrate a shift towards a basal-like transcriptional program among treated samples. We observe decreased ligand-receptor interactions in treated samples, particularly between TIGIT on CD8 + T cells and its receptor on cancer cells, and identify TIGIT as the major inhibitory checkpoint molecule of CD8 + T cells. Our results suggest that chemotherapy profoundly impacts the PDAC TME and may promote resistance to immunotherapy.
Funder
Center for Strategic Scientific Initiatives, National Cancer Institute
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
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