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.
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致癌 KRAS 信号通过激活 CD47 驱动肺腺癌逃避先天免疫监视
DOI：
10.1172/jci153470
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发表时间：
2023-01-17
期刊：
影响因子：
--
通讯作者：
Chen X
中科院分区：
文献类型：
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作者：
Hu H;Cheng R;Wang Y;Wang X;Wu J;Kong Y;Zhan S;Zhou Z;Zhu H;Yu R;Liang G;Wang Q;Zhu X;Zhang CY;Yin R;Yan C;Chen X
KRAS 是人类癌症中最常激活的癌基因之一。尽管KRAS突变在肿瘤发生和肿瘤维持中的作用已被广泛研究，但KRAS与肿瘤免疫微环境之间的关系尚不完全清楚。在这里，我们确定了 KRAS 在驱动肿瘤逃避先天免疫监视中的作用。在来自患者的肺腺癌样本和Kras驱动的肺癌基因小鼠模型中，突变型KRAS激活了分化簇47（CD47）的表达，这是癌细胞中的一种抗吞噬信号，导致巨噬细胞对癌细胞的吞噬作用减少。从机制上讲，突变型 KRAS 激活 PI3K/STAT3 信号传导，从而抑制 miR-34a 表达并缓解 miR-34a 对 CD47 的转录后抑制。在 3 个独立的肺癌患者队列中，KRAS 突变状态与 CD47 表达呈正相关。在治疗上，用 KRAS siRNA、KRASG12C 抑制剂 AMG 510 或 miR-34a 模拟物破坏 KRAS/CD47 信号轴可抑制 CD47 表达，增强巨噬细胞的吞噬能力，并恢复先天免疫监视。我们的结果揭示了活性 KRAS 与先天免疫逃避之间的直接机制联系，并将 CD47 确定为 KRAS 介导的免疫抑制肿瘤微环境的主要效应器。
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.