Tobacco Smoking-Associated Alterations in the Immune Microenvironment of Squamous Cell Carcinomas
Tobacco Smoking-Associated Alterations in the Immune Microenvironment of Squamous Cell Carcinomas
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DOI：
10.1093/jnci/djy060
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发表时间：
2018-12-01
影响因子：
10.3
通讯作者：
Morris, Luc G. T.
中科院分区：
文献类型：
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作者：
Desrichard, Alexis;Kuo, Fengshen;Morris, Luc G. T.
背景：吸烟会造成DNA损伤，诱导突变，并可能改变肿瘤免疫微环境。这些类型的遗传和免疫微环境改变是已知影响肿瘤对免疫治疗反应的关键因素。在这里，我们分析了吸烟的突变特征、肿瘤突变负荷和头颈部和肺鳞状细胞癌中免疫活性指标之间的关联。（HNSC; n = 287）和肺（LUSC; n = 130）鳞状细胞癌数据集和两个独立的基因表达数据集（HNSC，n = 136; LUSC，n = 75），我们检查了突变吸烟特征、突变计数、免疫细胞浸润、细胞溶解活性和干扰素-γ信号传导之间的关联。增加的突变吸烟特征与两个HNSC中统计学显著增加的总体突变负荷相关。（rho= 0.33，P = 1.01 x 10（-7））和LUSC（rho = 0.49，P = 2.80 x 10（-9））。在HNSC中，较高的突变吸烟特征与较低水平的免疫浸润（rho =-0.37，P = 1.29 x 10（-10））、细胞溶解活性（rho =-0.28，P = 4.07 x 10（-6））和干扰素-c通路信号传导（rho = 0.39，P = 3.20 x 10（-11））相关。在LUSC中，这些相关性被逆转（分别为rho = .19，P = .03; rho = .20，P = .02; rho = .18，P = .047）。吸烟高和吸烟低肿瘤之间的差异表达基因揭示了广泛的烟草诱导的免疫抑制在HNSC中，在与LUSC.Conclusions的吸烟者的肿瘤发炎的微环境：在鳞状细胞癌，遗传吸烟签名与较高的突变负荷，但可变的影响肿瘤免疫可能会发生，这取决于解剖部位。在HNSC中，吸烟主要是免疫抑制;在LUSC中，更多是促炎性的。肿瘤突变负荷和免疫微环境都影响免疫治疗的临床反应。因此，突变的吸烟特征可能与吸烟相关癌症的免疫学研究相关。
Background: Tobacco smoking creates DNA damage, inducing mutations and potentially altering the tumor immune microenvironment. These types of genetic and immune microenvironment alterations are critical factors known to affect tumor response to immunotherapy. Here we analyze the association between the mutational signature of tobacco smoking, tumor mutational load, and metrics of immune activity in squamous cell carcinomas arising in the head and neck and lung.Methods: Using RNA and DNA sequencing data from The Cancer Genome Atlas head and neck (HNSC; n = 287) and lung (LUSC; n = 130) squamous cell carcinoma data sets and two independent gene expression data sets (HNSC, n = 136; LUSC, n = 75), we examined associations between the mutational smoking signature, mutation count, immune cell infiltration, cytolytic activity, and interferon-gamma signaling.Results: An increasing mutational smoking signature was associated with statistically significantly increased overall mutational load in both HNSC (rho=.33, P = 1.01 x 10(-7)) and LUSC (rho = .49, P = 2.80 x 10(-9)). In HNSC, a higher mutational smoking signature was associated with lower levels of immune infiltration (rho = -.37, P = 1.29 x 10(-10)), cytolytic activity (rho = -.28, P = 4.07 x 10(-6)), and interferon-c pathway signaling (rho = .39, P = 3.20 x 10(-11)). In LUSC, these associations were reversed (rho = .19, P = .03; rho = .20, P = .02; and rho = .18, P = .047, respectively). Differentially expressed genes between smoking-high and smoking-low tumors revealed broad tobacco-induced immunosuppression in HNSC, in contrast to a tumor-inflamed microenvironment in smokers with LUSC.Conclusions: In squamous cell carcinomas, the genetic smoking signature is associated with higher mutational load, but variable effects on tumor immunity can occur, depending on anatomic site. In HNSC, smoking is predominantly immunosuppressive; in LUSC, more pro-inflammatory. Both tumor mutation load and immune microenvironment affect clinical response to immunotherapy. Thus, the mutational smoking signature is likely to have relevance for immunotherapeutic investigation in smoking-associated cancers.