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KRAS drives immune evasion in a genetic model of pancreatic cancer (Combined)

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

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 sup- pression 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.

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Species: mouse
Number of cells: 43788
Number of downloads: 6
Study size: 837MB
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Immunology 
immuno-oncology 
pancreatic ductal adenocarcinoma 
pancreas 
Immune evasion 
Immune suppression