Song Seung Geun, Kim Sehui, Koh Jaemoon, Yim Jeemin, Han Bogyeong, Kim Young A, Jeon Yoon Kyung, Chung Doo Hyun
Department of Pathology, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.
Laboratory of Immune Regulation, Department of Biomedical Sciences, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.
Cancer Immunol Immunother. 2021 Jul;70(7):2035-2048. doi: 10.1007/s00262-020-02840-0. Epub 2021 Jan 9.
To evaluate the characteristics of the tumor immune-microenvironment in brain metastases of non-small-cell lung cancer (NSCLC), we investigated the immunophenotype of primary NSCLC and its brain metastasis.
Expression profiling of 770 immune-related genes in 28 tissues from primary and brain metastases of NSCLC was performed using the NanoString nCounter PanCancer Immune Profiling Panel. The immune cell profiles were validated by immunohistochemistry of 42 matched samples.
Based on unsupervised clustering and principal component analysis of the immune-related gene expression profile, tumors were primarily clustered according to the involved organ and further grouped according to the EGFR mutation status. Fifty-four genes were significantly differentially expressed between primary and brain metastatic tumors. Clustering using these genes showed that tumors harboring mutated EGFR tended to be grouped together in the brain. Pathway analysis revealed that various immune-related functions involving immune regulation, T cell activity, and chemokines were enriched in primary tumors compared to brain metastases. Diverse immune-related pathways were upregulated in brain metastases of EGFR-mutated compared to EGFR-wild-type adenocarcinoma, but not in primary tumors. The interferon-γ-related gene signature was significantly decreased in brain metastases. The anti-inflammatory markers TOLLIP and HLA-G were upregulated in brain metastases. The proportions of most immune cell subsets were decreased in brain metastases, but those of macrophages and CD56dim-NK-cells were increased, as was the ratios of CD163M2- to iNOSM1-macrophages and NCR1NK-cells to CD3T cells.
Our findings illustrate the immune landscape of brain metastases from NSCLC and reveal potential therapeutic strategies targeting cellular and non-cellular components of the tumor immune-microenvironment.
为评估非小细胞肺癌（NSCLC）脑转移瘤的肿瘤免疫微环境特征，我们研究了原发性NSCLC及其脑转移瘤的免疫表型。
使用NanoString nCounter泛癌免疫分析面板对28例NSCLC原发灶和脑转移灶组织中的770个免疫相关基因进行表达谱分析。通过对42例匹配样本进行免疫组化验证免疫细胞谱。
基于免疫相关基因表达谱的无监督聚类和主成分分析，肿瘤主要根据受累器官聚类，并进一步根据表皮生长因子受体（EGFR）突变状态分组。原发肿瘤和脑转移瘤之间有54个基因存在显著差异表达。使用这些基因进行聚类分析表明，携带EGFR突变的肿瘤在脑内倾向于聚集在一起。通路分析显示，与脑转移瘤相比，原发性肿瘤中多种免疫相关功能（包括免疫调节、T细胞活性和趋化因子）更为丰富。与EGFR野生型腺癌相比，EGFR突变型腺癌脑转移瘤中多种免疫相关通路上调，但原发性肿瘤中未出现这种情况。脑转移瘤中γ-干扰素相关基因特征显著降低。抗炎标志物Toll相互作用蛋白（TOLLIP）和人类白细胞抗原G（HLA-G）在脑转移瘤中上调。脑转移瘤中大多数免疫细胞亚群的比例降低，但巨噬细胞和CD56dim自然杀伤细胞（NK细胞）的比例增加，CD163M2+巨噬细胞与诱导型一氧化氮合酶M1+巨噬细胞的比例以及自然细胞毒性受体1+NK细胞与CD3+T细胞的比例也增加。
我们的研究结果阐明了NSCLC脑转移瘤的免疫格局，并揭示了针对肿瘤免疫微环境中细胞和非细胞成分的潜在治疗策略。
