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Published on: November 19, 2019
KRAS drives immune evasion in a genetic model of pancreatic cancer
Irene Ischenko1, Stephen D'Amico1, Manisha Rao2
1Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY, USA.
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.
Insights
Oncogenic KRAS drives immune evasion in pancreatic cancer. Reducing KRAS activity boosts antitumor immunity, revealing BRAF and MYC as key targets for immune suppression in KRAS-driven cancers.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Immune evasion is a key characteristic of KRAS-driven cancers, but its mechanisms are not fully understood.
- Understanding these mechanisms is crucial for developing effective cancer therapies.
Purpose of the Study:
- To investigate the role of KRAS in immune evasion in pancreatic ductal adenocarcinoma (PDAC).
- To identify molecular mediators of KRAS-driven tumor immune suppression.
Main Methods:
- Utilized a mouse model of pancreatic ductal adenocarcinoma.
- Employed CRISPR-mediated genome editing to inactivate KRAS.
- Assessed tumor growth and immune response in both immunodeficient and syngeneic wild-type mice.
Main Results:
- KRAS inactivation reduced tumor growth dependence at advanced stages, correlating with suppressed antitumor immunity.
- KRAS-deficient cells failed to evade the immune system in wild-type mice, eliciting a strong antitumor response.
- Identified BRAF and MYC as critical mediators of KRAS-driven immune suppression; BRAF loss inhibited tumor growth.
- Observed a more vigorous immune environment associated with reduced KRAS activity in human PDAC.
Conclusions:
- Oncogenic KRAS plays a significant role in suppressing antitumor immunity in PDAC.
- BRAF and MYC are key targets for overcoming KRAS-driven immune evasion.
- Lowering KRAS activity may enhance anti-PDAC immune responses.
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