The Immune Contexture Associates with the Genomic Landscape in Lung Adenomatous Premalignancy
The Immune Contexture Associates with the Genomic Landscape in Lung Adenomatous Premalignancy
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DOI：
10.1158/0008-5472.can-19-0153
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发表时间：
2019-10-01
期刊：
影响因子：
11.2
通讯作者：
Dubinett, Steven M.
中科院分区：
文献类型：
--
作者：
Krysan, Kostyantyn;Tran, Linh M.;Dubinett, Steven M.
肺损伤领域的上皮细胞可以引起不同的癌前病变，这些病变可能带有独特的遗传异常。这些病变的一部分可能逃脱免疫监视并进展为浸润性癌症；然而，可能预测进展的突变图景尚未确定。了解癌前病变的成分和相关的微环境对于了解肿瘤的发生和发展有效的预防和拦截策略至关重要。为了确定腺瘤前病变及其相关肺腺癌中的体细胞突变和免疫细胞浸润的程度，我们对41例肺癌切除标本进行了外显子序列测定，其中包括癌前非典型增生病变、15例腺原位癌和55例浸润性腺癌及癌旁正常肺组织。我们将发生在癌前病变和相关肿瘤中的非同义体细胞突变定义为进展相关突变，其预测的新抗原与癌前病变中CD8(+)和CD4(+)T细胞的渗透以及PD-L1的上调高度相关，这表明对这些新抗原存在适应性免疫反应。每个患者都有一个独特的体细胞突变和相关新抗原的谱系。总之，这些结果为肺部癌前病变的突变异质性、途径失调和免疫识别提供了证据。意义：这些发现确定了与进展相关的体细胞突变、致癌途径，以及在腺瘤癌前病变中突变景观和获得性免疫反应之间的关联。
Epithelial cells in the field of lung injury can give rise to distinct premalignant lesions that may bear unique genetic aberrations. A subset of these lesions may escape immune surveillance and progress to invasive cancer; however, the mutational landscape that may predict progression has not been determined. Knowledge of premalignant lesion composition and the associated microenvironment is critical for understanding tumorigenesis and the development of effective preventive and interception strategies. To identify somatic mutations and the extent of immune cell infiltration in adenomatous premalignancy and associated lung adenocarcinomas, we sequenced exomes from 41 lung cancer resection specimens, including 89 premalignant atypical adenomatous hyperplasia lesions, 15 adenocarcinomas in situ, and 55 invasive adenocarcinomas and their adjacent normal lung tissues. We defined nonsynonymous somatic mutations occurring in both premalignancy and the associated tumor as progression-associated mutations whose predicted neoantigens were highly correlated with infiltration of CD8(+) and CD4(+) T cells as well as upregulation of PD-L1 in premalignant lesions, suggesting the presence of an adaptive immune response to these neoantigens. Each patient had a unique repertoire of somatic mutations and associated neoantigens. Collectively, these results provide evidence for mutational heterogeneity, pathway dysregulation, and immune recognition in pulmonary premalignancy.Significance: These findings identify progression-associated somatic mutations, oncogenic pathways, and association between the mutational landscape and adaptive immune responses in adenomatous premalignancy.