IL6 Blockade Reprograms the Lung Tumor Microenvironment to Limit the Development and Progression of K-ras-Mutant Lung Cancer.
IL6 Blockade Reprograms the Lung Tumor Microenvironment to Limit the Development and Progression of K-ras-Mutant Lung Cancer.
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DOI：
10.1158/0008-5472.can-15-2840
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发表时间：
2016-06-01
期刊：
影响因子：
11.2
通讯作者：
Moghaddam SJ
中科院分区：
文献类型：
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作者：
Caetano MS;Zhang H;Cumpian AM;Gong L;Unver N;Ostrin EJ;Daliri S;Chang SH;Ochoa CE;Hanash S;Behrens C;Wistuba II;Sternberg C;Kadara H;Ferreira CG;Watowich SS;Moghaddam SJ
激活K-ras突变是肺癌中最常见的致癌改变。不幸的是，针对K-ras突变肺肿瘤的尝试迄今为止都失败了，这清楚地表明需要新的方法来治疗具有这种分子特征的患者。我们之前已经在K-ras突变型肺肿瘤中发现NF-κB的激活、IL-6的释放以及其应答转录因子STAT3的激活，而慢性阻塞性肺疾病（COPD）型气道炎症对肿瘤的增强作用进一步放大了这一点。这些发现表明，这种炎症途径在K-ras突变型肺肿瘤发生及其COPD增强中起重要作用。因此，在没有或存在copd型气道炎症的K-ras突变肺癌小鼠模型中，我们使用单克隆抗IL-6抗体阻断IL-6。IL-6阻断显著抑制肺癌促进、肿瘤细胞内在STAT3激活、肿瘤细胞增殖和血管生成标志物。此外，IL-6抑制降低了促肿瘤2型分子（精氨酸酶1、Fizz 1、Mgl和IDO）的表达，M2型巨噬细胞和G-MDSCs的数量，以及促肿瘤T调节/T辅助17细胞的反应。这伴随着抗肿瘤1型分子（Nos2）的表达增加，抗肿瘤T辅助1/CD8 T细胞反应增加。我们的研究表明，IL-6阻断不仅对肿瘤细胞具有直接的内在抑制作用，而且通过改变促肿瘤和抗肿瘤免疫细胞之间的相对比例，将肺微环境重新教育到抗肿瘤表型。这一信息介绍了IL-6作为预防和治疗K-ras突变肺肿瘤的潜在药物靶点。
Activating mutations of K-ras are the most common oncogenic alterations found in lung cancer. Unfortunately, attempts to target K-ras mutant lung tumors have thus far failed, clearly indicating the need for new approaches in patients with this molecular profile. We have previously shown NF-κB activation, release of IL-6, and activation of its responsive transcription factor STAT3 in K-ras mutant lung tumors, which was further amplified by the tumor enhancing effect of chronic obstructive pulmonary disease (COPD)-type airway inflammation. These findings suggest an essential role for this inflammatory pathway in K-ras mutant lung tumorigenesis and its enhancement by COPD. Therefore, here we blocked IL-6 using a monoclonal anti-IL-6 antibody in a K-ras mutant mouse model of lung cancer in the absence or presence of COPD-type airway inflammation. IL-6 blockade significantly inhibited lung cancer promotion, tumor cell intrinsic STAT3 activation, tumor cell proliferation, and angiogenesis markers. Moreover, IL-6 inhibition reduced expression of pro-tumor type 2 molecules (Arginase 1, Fizz 1, Mgl, and IDO), number of M2 type macrophages and G-MDSCs, and pro-tumor T-regulatory/T helper 17 cell responses. This was accompanied by increased expression of anti-tumor type 1 molecule (Nos2), and anti-tumor T helper 1/CD8 T cell responses. Our study demonstrates that IL-6 blockade not only has direct intrinsic inhibitory effect on tumor cells, but also re-educates the lung microenvironment toward an anti-tumor phenotype by altering the relative proportion between pro-tumor and anti-tumor immune cells. This information introduces IL-6 as a potential druggable target for prevention and treatment of K-ras mutant lung tumors.