AXL Targeting Overcomes Human Lung Cancer Cell Resistance to NK- and CTL-Mediated Cytotoxicity
AXL Targeting Overcomes Human Lung Cancer Cell Resistance to NK- and CTL-Mediated Cytotoxicity
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DOI：
10.1158/2326-6066.cir-18-0903
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发表时间：
2019-09
影响因子：
10.1
通讯作者：
S. Terry;Abdérémane Abdou;A. Engelsen;Stéphanie Buart;P. Dessen;Stéphanie Corgnac;D. Collares;G. Meurice;G. Gausdal;V. Baud;P. Saintigny;J. Lorens;J. Thiery;F. Mami-Chouaib;S. Chouaib
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文献类型：
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作者：
S. Terry;Abdérémane Abdou;A. Engelsen;Stéphanie Buart;P. Dessen;Stéphanie Corgnac;D. Collares;G. Meurice;G. Gausdal;V. Baud;P. Saintigny;J. Lorens;J. Thiery;F. Mami-Chouaib;S. Chouaib
表达 AXL（一种与上皮间质转化相关的酪氨酸激酶受体）的肺癌细胞对细胞毒性淋巴细胞攻击具有内在抵抗力。 AXL 蛋白可能代表增强癌细胞抗肿瘤免疫敏感性的治疗靶点。免疫抵抗可能由遗传不稳定性和肿瘤异质性引起。缺氧等微环境应激和各种抵抗机制促进癌细胞可塑性。 AXL 是 TAM（Tyro3、Axl 和 Mer）受体酪氨酸激酶家族的成员，在人类癌症中广泛表达，并因其在细胞可塑性和耐药性中的作用而日益得到认可。为了研究免疫抵抗机制，我们研究了源自缺氧诱导的肿瘤可塑性模型的多个人类肺癌克隆，这些克隆表现出间充质或上皮特征。我们证明 AXL 表达在间充质肺癌克隆中增加。细胞中 AXL 的表达与癌细胞对自然杀伤 (NK) 和细胞毒性 T 淋巴细胞 (CTL) 介导的杀伤的内在抵抗力增加相关。一种靶向 AXL 的小分子使间充质肺癌细胞对细胞毒性淋巴细胞介导的杀伤变得敏感。从机制上讲，我们发现 AXL 依赖性免疫抵抗的减弱涉及一个分子网络，该网络包括 NF-κB 激活、ICAM1 表达增加、ULBP1 表达上调以及 MAPK 抑制。在两个非小细胞肺癌 (NSCLC) 队列中，较高的 ICAM1 和 ULBP1 肿瘤表达与患者生存率的提高相关。这些结果揭示了 AXL 介导的免疫逃逸调节途径，表明 AXL 作为肿瘤对 NK 和 CTL 免疫抵抗的候选生物标志物，并支持 AXL 靶向优化 NSCLC 的免疫反应。
Lung carcinoma cells that express AXL, a tyrosine kinase receptor associated with epithelial-to-mesenchymal transition, have intrinsic resistance to cytotoxic lymphocyte attacks. AXL protein may represent a therapeutic target to enhance cancer cell susceptibility to antitumor immunity. Immune resistance may arise from both genetic instability and tumor heterogeneity. Microenvironmental stresses such as hypoxia and various resistance mechanisms promote carcinoma cell plasticity. AXL, a member of the TAM (Tyro3, Axl, and Mer) receptor tyrosine kinase family, is widely expressed in human cancers and increasingly recognized for its role in cell plasticity and drug resistance. To investigate mechanisms of immune resistance, we studied multiple human lung cancer clones derived from a model of hypoxia-induced tumor plasticity that exhibited mesenchymal or epithelial features. We demonstrate that AXL expression is increased in mesenchymal lung cancer clones. Expression of AXL in the cells correlated with increased cancer cell–intrinsic resistance to both natural killer (NK)– and cytotoxic T lymphocyte (CTL)–mediated killing. A small-molecule targeting AXL sensitized mesenchymal lung cancer cells to cytotoxic lymphocyte–mediated killing. Mechanistically, we showed that attenuation of AXL-dependent immune resistance involved a molecular network comprising NF-κB activation, increased ICAM1 expression, and upregulation of ULBP1 expression coupled with MAPK inhibition. Higher ICAM1 and ULBP1 tumor expression correlated with improved patient survival in two non–small cell lung cancer (NSCLC) cohorts. These results reveal an AXL-mediated immune-escape regulatory pathway, suggest AXL as a candidate biomarker for tumor resistance to NK and CTL immunity, and support AXL targeting to optimize immune response in NSCLC.