2. Academic Validation
  3. Plasticity-induced repression of Irf6 underlies acquired resistance to cancer immunotherapy in pancreatic ductal adenocarcinoma

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

  • Nat Commun. 2024 Feb 20;15(1):1532. doi: 10.1038/s41467-024-46048-7.
Il-Kyu Kim # 1 2,  Mark S Diamond # 1 2,  Salina Yuan # 1 2,  Samantha B Kemp 1 2,  Benjamin M Kahn 1 2 3,  Qinglan Li 4 5,  Jeffrey H Lin 1 2,  Jinyang Li 1 2,  Robert J Norgard 1 2,  Stacy K Thomas 1 2,  Maria Merolle 1 2,  Takeshi Katsuda 1 2,  John W Tobias 6,  Timour Baslan 7,  Katerina Politi 8 9 10,  Robert H Vonderheide 11 12 13,  Ben Z Stanger 14 15 16
Affiliations

Affiliations

  • 1 Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 2 Abramson Cancer Center and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 3 Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 4 Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 5 Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 6 Penn Genomic Analysis Core, University of Pennsylvania, Philadelphia, PA, USA.
  • 7 Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 8 Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA.
  • 9 Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
  • 10 Section of Medical Oncology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
  • 11 Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. rhv@upenn.edu.
  • 12 Abramson Cancer Center and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. rhv@upenn.edu.
  • 13 Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA, USA. rhv@upenn.edu.
  • 14 Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. bstanger@upenn.edu.
  • 15 Abramson Cancer Center and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. bstanger@upenn.edu.
  • 16 Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. bstanger@upenn.edu.
  • # Contributed equally.
PMID: 38378697 DOI: 10.1038/s41467-024-46048-7
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.

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