Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman 4184, United Arab Emirates.
National Center for Biological Sciences, Tata Institute of Fundamental Research, Bangalore 560065, India.
Int J Mol Sci. 2022 Jun 20;23(12):6848. doi: 10.3390/ijms23126848.
The role of autophagy in lung cancer cells exposed to waterpipe smoke (WPS) is not known. Because of the important role of autophagy in tumor resistance and progression, we investigated its relationship with WP smoking. We first showed that WPS activated autophagy, as reflected by LC3 processing, in lung cancer cell lines. The autophagy response in smokers with lung adenocarcinoma, as compared to non-smokers with lung adenocarcinoma, was investigated further using the TCGA lung adenocarcinoma bulk RNA-seq dataset with the available patient metadata on smoking status. The results, based on a machine learning classification model using Random Forest, indicate that smokers have an increase in autophagy-activating genes. Comparative analysis of lung adenocarcinoma molecular signatures in affected patients with a long-term active exposure to smoke compared to non-smoker patients indicates a higher tumor mutational burden, a higher CD8+ T-cell level and a lower dysfunction level in smokers. While the expression of the checkpoint genes tested-PD-1, PD-L1, PD-L2 and CTLA-4-remains unchanged between smokers and non-smokers, B7-1, B7-2, IDO1 and CD200R1 were found to be higher in non-smokers than smokers. Because multiple factors in the tumor microenvironment dictate the success of immunotherapy, in addition to the expression of immune checkpoint genes, our analysis explains why patients who are smokers with lung adenocarcinoma respond better to immunotherapy, even though there are no relative differences in immune checkpoint genes in the two groups. Therefore, targeting autophagy in lung adenocarcinoma patients, in combination with checkpoint inhibitor-targeted therapies or chemotherapy, should be considered in smoker patients with lung adenocarcinoma.
自噬在暴露于水烟（WPS）的肺癌细胞中的作用尚不清楚。由于自噬在肿瘤耐药和进展中起着重要作用，我们研究了其与 WP 吸烟的关系。我们首先表明，WPS 激活了肺癌细胞系中的自噬，如 LC3 加工所反映的。使用 TCGA 肺腺癌批量 RNA-seq 数据集进一步研究了吸烟者与肺腺癌非吸烟者之间的自噬反应，该数据集具有吸烟状态的可用患者元数据。基于使用随机森林的机器学习分类模型的结果表明，吸烟者的自噬激活基因增加。与非吸烟者相比，长期暴露于烟雾的受影响患者的肺腺癌分子特征的比较分析表明，吸烟者的肿瘤突变负担更高，CD8+T 细胞水平更高，功能失调水平更低。虽然在吸烟者和非吸烟者之间，测试的检查点基因（PD-1、PD-L1、PD-L2 和 CTLA-4）的表达保持不变，但发现非吸烟者的 B7-1、B7-2、IDO1 和 CD200R1 表达高于吸烟者。由于肿瘤微环境中的多种因素决定了免疫疗法的成败，除了免疫检查点基因的表达外，我们的分析解释了为什么吸烟的肺腺癌患者对免疫疗法的反应更好，尽管两组之间免疫检查点基因没有相对差异。因此，在患有肺腺癌的吸烟者患者中，应考虑将自噬靶向与检查点抑制剂靶向治疗或化疗相结合。
