Plasticity-induced repression of Irf6 underlies acquired resistance to cancer immunotherapy in pancreatic ductal adenocarcinoma

Il-Kyu Kim, Mark S. Diamond, Salina Yuan, Samantha B. Kemp, Benjamin M. Kahn, Qinglan Li, Jeffrey H. Lin, Jinyang Li, Robert J. Norgard, Stacy K. Thomas, Maria Merolle, Takeshi Katsuda, John W. Tobias, Timour Baslan, Katerina Politi, Robert H. Vonderheide () and Ben Z. Stanger ()
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Il-Kyu Kim: Perelman School of Medicine, University of Pennsylvania
Mark S. Diamond: Perelman School of Medicine, University of Pennsylvania
Salina Yuan: Perelman School of Medicine, University of Pennsylvania
Samantha B. Kemp: Perelman School of Medicine, University of Pennsylvania
Benjamin M. Kahn: Perelman School of Medicine, University of Pennsylvania
Qinglan Li: Perelman School of Medicine, University of Pennsylvania
Jeffrey H. Lin: Perelman School of Medicine, University of Pennsylvania
Jinyang Li: Perelman School of Medicine, University of Pennsylvania
Robert J. Norgard: Perelman School of Medicine, University of Pennsylvania
Stacy K. Thomas: Perelman School of Medicine, University of Pennsylvania
Maria Merolle: Perelman School of Medicine, University of Pennsylvania
Takeshi Katsuda: Perelman School of Medicine, University of Pennsylvania
John W. Tobias: University of Pennsylvania
Timour Baslan: School of Veterinary Medicine, University of Pennsylvania
Katerina Politi: Yale School of Medicine
Robert H. Vonderheide: Perelman School of Medicine, University of Pennsylvania
Ben Z. Stanger: Perelman School of Medicine, University of Pennsylvania

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Acquired resistance to immunotherapy remains a critical yet incompletely understood biological mechanism. Here, using a mouse model of pancreatic ductal adenocarcinoma (PDAC) to study tumor relapse following immunotherapy-induced responses, we find that resistance is reproducibly associated with an epithelial-to-mesenchymal transition (EMT), with EMT-transcription factors ZEB1 and SNAIL functioning as master genetic and epigenetic regulators of this effect. Acquired resistance in this model is not due to immunosuppression in the tumor immune microenvironment, disruptions in the antigen presentation machinery, or altered expression of immune checkpoints. Rather, resistance is due to a tumor cell-intrinsic defect in T-cell killing. Molecularly, EMT leads to the epigenetic and transcriptional silencing of interferon regulatory factor 6 (Irf6), rendering tumor cells less sensitive to the pro-apoptotic effects of TNF-α. These findings indicate that acquired resistance to immunotherapy may be mediated by programs distinct from those governing primary resistance, including plasticity programs that render tumor cells impervious to T-cell killing.

Date: 2024
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DOI: 10.1038/s41467-024-46048-7

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