Single-cell RNA sequencing reveals the effects of chemotherapy on human pancreatic adenocarcinoma and its tumor microenvironment

Gregor Werba, Daniel Weissinger, Emily A. Kawaler, Ende Zhao, Despoina Kalfakakou, Surajit Dhara, Lidong Wang, Heather B. Lim, Grace Oh, Xiaohong Jing, Nina Beri, Lauren Khanna, Tamas Gonda, Paul Oberstein, Cristina Hajdu, Cynthia Loomis, Adriana Heguy, Mara H. Sherman, Amanda W. Lund, Theodore H. Welling, Igor Dolgalev, Aristotelis Tsirigos () and Diane M. Simeone ()
Additional contact information
Gregor Werba: NYU Langone Health
Daniel Weissinger: NYU Langone Health
Emily A. Kawaler: NYU Langone Health
Ende Zhao: NYU Langone Health
Despoina Kalfakakou: NYU Langone Health
Surajit Dhara: NYU Langone Health
Lidong Wang: NYU Langone Health
Heather B. Lim: NYU Langone Health
Grace Oh: NYU Langone Health
Xiaohong Jing: NYU Langone Health
Nina Beri: NYU Langone Health
Lauren Khanna: NYU Langone Health
Tamas Gonda: NYU Langone Health
Paul Oberstein: NYU Langone Health
Cristina Hajdu: NYU Langone Health
Cynthia Loomis: NYU Langone Health
Adriana Heguy: NYU Langone Health
Mara H. Sherman: Oregon Health Sciences University
Amanda W. Lund: NYU Langone Health
Theodore H. Welling: NYU Langone Health
Igor Dolgalev: NYU Langone Health
Aristotelis Tsirigos: NYU Langone Health
Diane M. Simeone: NYU Langone Health

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract The 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.

Date: 2023
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DOI: 10.1038/s41467-023-36296-4

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