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

Author

Listed:
  • Il-Kyu Kim

    (Perelman School of Medicine, University of Pennsylvania
    Perelman School of Medicine, University of Pennsylvania)

  • Mark S. Diamond

    (Perelman School of Medicine, University of Pennsylvania
    Perelman School of Medicine, University of Pennsylvania)

  • Salina Yuan

    (Perelman School of Medicine, University of Pennsylvania
    Perelman School of Medicine, University of Pennsylvania)

  • Samantha B. Kemp

    (Perelman School of Medicine, University of Pennsylvania
    Perelman School of Medicine, University of Pennsylvania)

  • Benjamin M. Kahn

    (Perelman School of Medicine, University of Pennsylvania
    Perelman School of Medicine, University of Pennsylvania
    Perelman School of Medicine, University of Pennsylvania)

  • Qinglan Li

    (Perelman School of Medicine, University of Pennsylvania
    Perelman School of Medicine, University of Pennsylvania)

  • Jeffrey H. Lin

    (Perelman School of Medicine, University of Pennsylvania
    Perelman School of Medicine, University of Pennsylvania)

  • Jinyang Li

    (Perelman School of Medicine, University of Pennsylvania
    Perelman School of Medicine, University of Pennsylvania)

  • Robert J. Norgard

    (Perelman School of Medicine, University of Pennsylvania
    Perelman School of Medicine, University of Pennsylvania)

  • Stacy K. Thomas

    (Perelman School of Medicine, University of Pennsylvania
    Perelman School of Medicine, University of Pennsylvania)

  • Maria Merolle

    (Perelman School of Medicine, University of Pennsylvania
    Perelman School of Medicine, University of Pennsylvania)

  • Takeshi Katsuda

    (Perelman School of Medicine, University of Pennsylvania
    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
    Yale School of Medicine
    Yale School of Medicine)

  • Robert H. Vonderheide

    (Perelman School of Medicine, University of Pennsylvania
    Perelman School of Medicine, University of Pennsylvania
    University of Pennsylvania)

  • Ben Z. Stanger

    (Perelman School of Medicine, University of Pennsylvania
    Perelman School of Medicine, University of Pennsylvania
    Perelman School of Medicine, University of Pennsylvania)

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.

Suggested Citation

  • 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 & Jo, 2024. "Plasticity-induced repression of Irf6 underlies acquired resistance to cancer immunotherapy in pancreatic ductal adenocarcinoma," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46048-7
    DOI: 10.1038/s41467-024-46048-7
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    References listed on IDEAS

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    1. Limo Chen & Don L. Gibbons & Sangeeta Goswami & Maria Angelica Cortez & Young-Ho Ahn & Lauren A. Byers & Xuejun Zhang & Xiaohui Yi & David Dwyer & Wei Lin & Lixia Diao & Jing Wang & Jonathon D. Roybal, 2014. "Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression," Nature Communications, Nature, vol. 5(1), pages 1-12, December.
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