Oncogenic KRAS signaling drives evasion of innate immune surveillance in lung adenocarcinoma by activating CD47

Citations Over TimeTop 10% of 2022 papers

Abstract

KRAS is one of the most frequently activated oncogenes in human cancers. Although the role of KRAS mutation in tumorigenesis and tumor maintenance has been extensively studied, the relationship between KRAS and the tumor immune microenvironment is not fully understood. Here, we identified a role of KRAS in driving tumor evasion from innate immune surveillance. In samples of lung adenocarcinoma from patients and Kras-driven genetic mouse models of lung cancer, mutant KRAS activated the expression of cluster of differentiation 47 (CD47), an antiphagocytic signal in cancer cells, leading to decreased phagocytosis of cancer cells by macrophages. Mechanistically, mutant KRAS activated PI3K/STAT3 signaling, which restrained miR-34a expression and relieved the posttranscriptional repression of miR-34a on CD47. In 3 independent cohorts of patients with lung cancer, the KRAS mutation status positively correlated with CD47 expression. Therapeutically, disruption of the KRAS/CD47 signaling axis with KRAS siRNA, the KRAS(G12C) inhibitor AMG 510, or a miR-34a mimic suppressed CD47 expression, enhanced the phagocytic capacity of macrophages, and restored innate immune surveillance. Our results reveal a direct mechanistic link between active KRAS and innate immune evasion and identify CD47 as a major effector underlying the KRAS-mediated immunosuppressive tumor microenvironment.

Related Papers

• → Molecular profile of KRAS G12C-mutant colorectal and non-small-cell lung cancer(2021)37 cited
• → Assessing the significance of KRAS G12C mutation: Clinicopathologic features, treatments, and survival outcomes in a real-world KRAS mutant non-small cell lung cancer cohort.(2020)3 cited
• → Molecular profile of KRAS G12C-mutant colorectal and non-small-cell lung cancer(2020)2 cited
• → Lung Cancer and <i>KRAS</i> -Its Molecular Biology/Genetics and Therapeutic Strategy-(2022)
• → 127P RAS, RAF and NF1 oncogenic mutations in KRAS-mutated lung adenocarcinoma(2022)