KRAS drives immune evasion in a genetic model of pancreatic cancer

Irene Ischenko, Stephen D’Amico, Manisha Rao, Jinyu Li, Michael J. Hayman, Scott Powers, Oleksi Petrenko () and Nancy C. Reich ()
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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

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21736-w

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DOI: 10.1038/s41467-021-21736-w

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