Single-Cell RNA Sequencing Reveals the Effects of Chemotherapy on Human Pancreatic Adenocarcinoma and its Tumor Microenvironment

Werba, G.; Weissinger, D.; Kawaler, E. A.; Zhao, E.; Kalfakakou, D.; Dhara, S.; Oh, G.; Jing, X.; Beri, N.; Khanna, L.; Gonda, T.; Oberstein, P.; Hajdu, C.; Loomis, C. A.; Heguy, A.; Sherman, M. H.; Lund, A. W.; Welling, T. H.; Dolgalev, I.; Tsirigos, A.; Simeone, D. M.

doi:10.1101/2022.05.24.493132

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bioRxiv · 10.1101/2022.05.24.493132

Single-Cell RNA Sequencing Reveals the Effects of Chemotherapy on Human Pancreatic Adenocarcinoma and its Tumor Microenvironment

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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. We performed single-cell RNA sequencing on freshly collected human PDAC samples either before or after chemotherapy. Overall, we found 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 exhibited similar transcriptional responses to chemotherapy, and did not demonstrate a shift towards a basal-like transcriptional program among treated samples. We observed decreased ligand-receptor interactions in treated samples, particularly TIGIT on CD8+ T cells and its receptor on cancer cells, and identified 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.

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Werba, G., Weissinger, D., Kawaler, E. A., Zhao, E., Kalfakakou, D., Dhara, S., Oh, G., Jing, X., Beri, N., Khanna, L., Gonda, T., Oberstein, P., Hajdu, C., Loomis, C. A., Heguy, A., Sherman, M. H., Lund, A. W., Welling, T. H., Dolgalev, I., Tsirigos, A., Simeone, D. M.. 2022-05-25. Single-Cell RNA Sequencing Reveals the Effects of Chemotherapy on Human Pancreatic Adenocarcinoma and its Tumor Microenvironment. https://doi.org/10.1101/2022.05.24.493132

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