Kim Ahreum, Lim Sun Min, Kim Joo-Hang, Seo Jeong-Sun
Department of Medicine, CHA University School of Medicine, Seongnam, South Korea.
Precision Medicine Center, Seoul National University Bundang Hospital, Seongnamsi, South Korea.
Front Immunol. 2021 Feb 25;12:598671. doi: 10.3389/fimmu.2021.598671. eCollection 2021.
Non-small-cell lung cancers (NSCLCs) are largely classified into lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), which have different therapeutic options according to its molecular profiles and immune checkpoint expression, especially PD-L1, which is a suppressive factor in the tumor microenvironment. The tumor microenvironment can be altered by the genomic mutations on specific innate immune genes as well as tumor suppressor genes, so it is essential to comprehend the association between tumor microenvironment and tumor suppressor genes to discover the promising immunotherapeutic strategy to overcome the resistance of immune check point blockade. In this study, we aimed to analyze how the somatic mutations in tumor suppressor genes affect the tumor immune microenvironment through a comprehensive analysis of mutational profiling on the representative tumor suppressor genes (, ) and immune gene expression in The Cancer Genome Atlas (TCGA) 155 lung squamous cell carcinoma (LUSC) and 196 lung adenocarcinoma (LUAD) samples. Several microenvironmental factors, such as the infiltrating immune and stromal cells, were suppressed by the mutated tumor suppressor genes in LUSC, unlike in the LUAD samples. In particular, infiltrating immune cells such as macrophage, neutrophil, and dendritic cells were significantly reduced in tumors with mutated tumor suppressor genes' group. In addition, the gene expressions for interleukin production and lymphocyte differentiation and were significantly down-regulated, which were key immune genes for the cross-talk between LUSC microenvironment and tumor suppressors. Therefore, we generated evidence that TSG mutations in LUSC have an impact on tumor immune microenvironment, which suggests that TSG non-mutated patients will have the more inflamed tumors and are more likely to respond to immune checkpoint blockade therapy.
非小细胞肺癌（NSCLCs）主要分为肺腺癌（LUAD）和肺鳞状细胞癌（LUSC），根据其分子特征和免疫检查点表达，尤其是肿瘤微环境中的抑制因子程序性死亡受体1（PD-L1），这两种癌症具有不同的治疗选择。肿瘤微环境可因特定先天免疫基因以及肿瘤抑制基因的基因组突变而改变，因此理解肿瘤微环境与肿瘤抑制基因之间的关联对于发现有前景的免疫治疗策略以克服免疫检查点阻断的耐药性至关重要。在本研究中，我们旨在通过对癌症基因组图谱（TCGA）中155例肺鳞状细胞癌（LUSC）和196例肺腺癌（LUAD）样本的代表性肿瘤抑制基因的突变谱和免疫基因表达进行综合分析，来分析肿瘤抑制基因中的体细胞突变如何影响肿瘤免疫微环境。与LUAD样本不同，LUSC中突变的肿瘤抑制基因抑制了几种微环境因素，如浸润性免疫细胞和基质细胞。特别是，在具有突变肿瘤抑制基因的肿瘤组中，巨噬细胞、中性粒细胞和树突状细胞等浸润性免疫细胞显著减少。此外，白细胞介素产生以及淋巴细胞分化相关的基因表达显著下调，这些是LUSC微环境与肿瘤抑制因子之间相互作用的关键免疫基因。因此，我们获得的证据表明，LUSC中的肿瘤抑制基因（TSG）突变对肿瘤免疫微环境有影响，这表明TSG未突变的患者肿瘤炎症更明显，更有可能对免疫检查点阻断疗法产生反应。
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