Smoker and non-smoker lung adenocarcinoma is characterized by distinct tumor immune microenvironments.
Smoker and non-smoker lung adenocarcinoma is characterized by distinct tumor immune microenvironments.
复制标题
吸烟者和非吸烟者肺腺癌的特点是不同的肿瘤免疫微环境。
DOI：
10.1080/2162402x.2018.1494677
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发表时间：
2018
期刊：
影响因子：
7.2
通讯作者：
Liu P
中科院分区：
文献类型：
--
作者：
Li X;Li J;Wu P;Zhou L;Lu B;Ying K;Chen E;Lu Y;Liu P
吸烟导致上皮细胞DNA损伤以及肺部免疫功能失调，这些共同促进了肺癌的发生和发展。然而，肿瘤浸润免疫细胞对肺癌生存的潜在作用机制以及它们在吸烟者和非吸烟者中的不同作用尚未得到充分研究。在此，我们对11个肺癌基因表达数据集进行了综合分析，包括1111例肺腺癌和200例相邻的正常肺组织样本。吸烟者和非吸烟者在肺癌发生过程中存在不同的通路改变。非吸烟患者的预后比吸烟患者更好。我们描述了肺腺癌中21种免疫细胞的组成模式，并揭示了免疫细胞组成与临床结果之间的复杂关联。有趣的是，我们发现了两类免疫细胞亚群，肥大细胞和CD4 +记忆T细胞，它们在静息和激活状态下与预后的关联完全相反。我们进一步发现，几种趋化因子及其相关受体（例如，CXCL11 - CX3CR1轴）在吸烟导致的肺部肿瘤中发生选择性改变，并且它们的丰度在吸烟者中与这些免疫细胞亚群的比例相关性比在非吸烟者中更强。肥大细胞和CD4 +记忆T细胞从静息状态转变为激活状态可能体现了吸烟在肿瘤发生和发展过程中诱导的一些重要过程。我们的研究结果表明，肥大细胞和CD4 +记忆T细胞的异常激活在吸烟诱导的肺部免疫功能失调中起着关键作用，这促进了肿瘤的发生和发展。
Tobacco smoking causes DNA damages in epithelial cells and immune dysfunction in the lung, which collectively contribute to lung carcinogenesis and progression. However, potential mechanisms by which tumor-infiltrating immune cells contribute to lung cancer survival and their differential contributions in ever-smokers and never-smokers are not well studied. Here, we performed integrative analysis of 11 lung cancer gene-expression datasets, including 1,111 lung adenocarcinomas and 200 adjacent normal lung samples. Distinct pathways were altered in lung carcinogenesis in ever-smokers and never-smokers. Never-smoker patients had a better outcome than ever-smoker patients. We characterized compositional patterns of 21 types of immune cells in lung adenocarcinomas and revealed the complex association between immune cell composition and clinical outcomes. Interestingly, we found two subsets of immune cells, mast cells and CD4+ memory T cells, which had completely opposite associations with outcomes in resting and activated status. We further discovered that several chemokines and their associated receptors (e.g., CXCL11-CX3CR1 axis) were selectively altered in lung tumors in response to cigarette smoking and their abundances showed stronger correlation with fractions of these immune subsets in ever-smokers than never-smokers. The status switched from the resting to activated forms in mast cells and CD4+ memory T cells might manifest some important processes induced by cigarette smoking during tumor development and progression. Our findings suggested that aberrant activation of mast cells and CD4+ memory T cells plays crucial roles in cigarette smoking-induced immune dysfunction in the lung, which contributes to tumor development and progression.