Oncogenic KRAS signaling drives evasion of innate immune surveillance in lung adenocarcinoma by activating CD47
Huanhuan Hu, … , Chao Yan, Xi Chen
Huanhuan Hu, … , Chao Yan, Xi Chen
Published November 22, 2022
Citation Information: J Clin Invest. 2023;133(2):e153470. https://doi.org/10.1172/JCI153470.
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Research Article Oncology Pulmonology

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

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 KRASG12C 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.

Authors

Huanhuan Hu, Rongjie Cheng, Yanbo Wang, Xiaojun Wang, Jianzhuang Wu, Yan Kong, Shoubin Zhan, Zhen Zhou, Hongyu Zhu, Ranran Yu, Gaoli Liang, Qingyan Wang, Xiaoju Zhu, Chen-Yu Zhang, Rong Yin, Chao Yan, Xi Chen

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Figure 4

miR-34a inhibits Kras-driven tumorigenesis and promotes macrophage infiltration in vivo.

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miR-34a inhibits Kras-driven tumorigenesis and promotes macrophage infil...
KrasLSL-G12D/+p53fl/fl mice were intratracheally administered adeno-Cre along with AAV-miR-34a (or control AAV-scrRNA) and AAV-CD47 (or AAV-control). (A) Kaplan-Meier survival analysis. (B) Representative micro-CT visualization of tumors 3 months after administration. (C) Representative H&E staining of lung sections. Scale bar: 2 mm. (D) Representative IHC staining for CD47 in lung sections. Scale bar: 20 μm. (E) Representative immunoblot of CD47 expression in lung tumors. (F) miR-34a levels in lung tumors (n = 5). (G) Immunofluorescence staining for CD11b (red), iNOS (purple), KRASG12D (green), and DAPI (blue) in lung tumors showing an increase in macrophage phagocytosis of tumor cells with AAV-miR-34a, which was rescued by AAV-CD47. Representative images and quantification results (n = 5 mice) are shown. Arrows indicate KRASG12D+iNOS+CD11b+ cells. Scale bar: 50 μm. Original magnification, ×40 (enlarged insets). Data are shown as the mean ± SEM. ***P < 0.001 and ****P < 0.0001, by 1-way ANOVA (F and G) or log-rank (Mantel-Cox) test (A).