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.

中文翻译：

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靶向AXL可以克服人类肺癌细胞对NK和CTL介导的细胞毒性的抵抗力。

免疫抗性可能源于基因的不稳定性和肿瘤的异质性。诸如缺氧和各种抵抗机制的微环境应力促进癌细胞的可塑性。AXL是TAM（Tyro3，Axl和Mer）受体酪氨酸激酶家族的成员，在人类癌症中得到广泛表达，并因其在细胞可塑性和耐药性中的作用而得到越来越多的认可。为了研究免疫抗性的机制，我们研究了多个人类肺癌克隆，这些克隆均来自低氧诱导的肿瘤可塑性模型，具有间充质或上皮细胞特征。我们证明间充质肺癌克隆中AXL表达增加。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）介导的杀伤的抵抗力增强相关。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作用敏感。从机理上讲，我们显示了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肿瘤表达与患者存活率提高相关。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免疫的抵抗力的候选生物标志物，并支持AXL靶向以优化NSCLC中的免疫反应。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肿瘤表达与患者存活率提高相关。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免疫力的候选生物标志物，并支持AXL靶向以优化NSCLC中的免疫反应。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肿瘤表达与患者存活率提高相关。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免疫力的候选生物标志物，并支持AXL靶向以优化NSCLC中的免疫反应。在两个非小细胞肺癌（NSCLC）队列中，较高的ICAM1和ULBP1肿瘤表达与患者存活率提高相关。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免疫的抵抗力的候选生物标志物，并支持AXL靶向以优化NSCLC中的免疫反应。在两个非小细胞肺癌（NSCLC）队列中，较高的ICAM1和ULBP1肿瘤表达与患者存活率提高相关。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免疫的抵抗力的候选生物标志物，并支持AXL靶向以优化NSCLC中的免疫反应。