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KRAS drives immune evasion in a genetic model of pancreatic cancer

Author

Listed:
  • Irene Ischenko

    (Stony Brook University)

  • Stephen D’Amico

    (Stony Brook University)

  • Manisha Rao

    (Stony Brook University)

  • Jinyu Li

    (Stony Brook University)

  • Michael J. Hayman

    (Stony Brook University)

  • Scott Powers

    (Stony Brook University)

  • Oleksi Petrenko

    (Stony Brook University)

  • Nancy C. Reich

    (Stony Brook University)

Abstract

Immune evasion is a hallmark of KRAS-driven cancers, but the underlying causes remain unresolved. Here, we use a mouse model of pancreatic ductal adenocarcinoma to inactivate KRAS by CRISPR-mediated genome editing. We demonstrate that at an advanced tumor stage, dependence on KRAS for tumor growth is reduced and is manifested in the suppression of antitumor immunity. KRAS-deficient cells retain the ability to form tumors in immunodeficient mice. However, they fail to evade the host immune system in syngeneic wild-type mice, triggering strong antitumor response. We uncover changes both in tumor cells and host immune cells attributable to oncogenic KRAS expression. We identify BRAF and MYC as key mediators of KRAS-driven tumor immune suppression and show that loss of BRAF effectively blocks tumor growth in mice. Applying our results to human PDAC we show that lowering KRAS activity is likewise associated with a more vigorous immune environment.

Suggested Citation

  • Irene Ischenko & Stephen D’Amico & Manisha Rao & Jinyu Li & Michael J. Hayman & Scott Powers & Oleksi Petrenko & Nancy C. Reich, 2021. "KRAS drives immune evasion in a genetic model of pancreatic cancer," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21736-w
    DOI: 10.1038/s41467-021-21736-w
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    Cited by:

    1. Lena Wiedmann & Francesca De Angelis Rigotti & Nuria Vaquero-Siguero & Elisa Donato & Elisa Espinet & Iris Moll & Elisenda Alsina-Sanchis & Hanibal Bohnenberger & Elena Fernandez-Florido & Ronja Mülfa, 2023. "HAPLN1 potentiates peritoneal metastasis in pancreatic cancer," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Xiaoyu Liu & Yaping Zhuang & Wei Huang & Zhuozhuo Wu & Yingjie Chen & Qungang Shan & Yuefang Zhang & Zhiyuan Wu & Xiaoyi Ding & Zilong Qiu & Wenguo Cui & Zhongmin Wang, 2023. "Interventional hydrogel microsphere vaccine as an immune amplifier for activated antitumour immunity after ablation therapy," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    3. Manuel Rodrigues & Giulia Vanoni & Pierre Loap & Coraline Dubot & Eleonora Timperi & Mathieu Minsat & Louis Bazire & Catherine Durdux & Virginie Fourchotte & Enora Laas & Nicolas Pouget & Zahra Castel, 2023. "Nivolumab plus chemoradiotherapy in locally-advanced cervical cancer: the NICOL phase 1 trial," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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