1. Academic Validation
  2. Oncogenic KRAS signaling drives evasion of innate immune surveillance in lung adenocarcinoma by activating CD47

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

  • J Clin Invest. 2022 Nov 22;e153470. doi: 10.1172/JCI153470.
Huanhuan Hu 1 Rongjie Cheng 1 Yanbo Wang 1 Xiaojun Wang 2 Jianzhuang Wu 1 Yan Kong 2 Shoubin Zhan 1 Zhen Zhou 1 Hongyu Zhu 2 Ranran Yu 1 Gaoli Liang 1 Qingyan Wang 1 Xiaoju Zhu 1 Chen-Yu Zhang 1 Rong Yin 2 Chao Yan 1 Xi Chen 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Pharmaceutical Sciences, School of Life Sciences, Nanjing University, Nanjing, China.
  • 2 Department of Thoracic Surgery, Jiangsu Cancer Hospital, Nanjing, China.
Abstract

KRAS is one of the most frequently activated oncogenes in human cancers. While 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. Herein, we identified a novel role of KRAS in driving tumor evasion from innate immune surveillance. In lung adenocarcinoma patient samples 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 post-transcriptional repression of miR-34a on CD47. In three independent lung Cancer patient cohorts, 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 miR-34a mimic suppressed CD47 expression, enhanced the phagocytic capacity of macrophages and restored innate immune surveillance. Our results revealed a direct mechanistic link between active KRAS and innate immune evasion and identified CD47 as a major effector underlying KRAS-mediated immunosuppressive tumor microenvironment.

Keywords

Cancer immunotherapy; Lung cancer; Oncogenes; Oncology; Pulmonology.

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