PURPOSE To provide a better understanding of the interplay between the immune system and brain metastases to advance therapeutic options for this life-threatening disease. EXPERIMENTAL DESIGN Tumor-infiltrating lymphocytes (TIL) were quantified by semiautomated whole-slide analysis in brain metastases from 81 lung adenocarcinomas. Multi-color staining enabled phenotyping of TILs (CD3, CD8, and FOXP3) on a single-cell resolution. Molecular determinants of the extent of TILs in brain metastases were analyzed by transcriptomics in a subset of 63 patients. Findings in lung adenocarcinoma brain metastases were related to published multi-omic primary lung adenocarcinoma The Cancer Genome Atlas data (n = 230) and single-cell RNA-sequencing (scRNA-seq) data (n = 52,698). RESULTS TIL numbers within tumor islands was an independent prognostic marker in patients with lung adenocarcinoma brain metastases. Comparative transcriptomics revealed that expression of three surfactant metabolism-related genes (SFTPA1, SFTPB, and NAPSA) was closely associated with TIL numbers. Their expression was not only prognostic in brain metastasis but also in primary lung adenocarcinoma. Correlation with scRNA-seq data revealed that brain metastases with high expression of surfactant genes might originate from tumor cells resembling alveolar type 2 cells. Methylome-based estimation of immune cell fractions in primary lung adenocarcinoma confirmed a positive association between lymphocyte infiltration and surfactant expression. Tumors with a high surfactant expression displayed a transcriptomic profile of an inflammatory microenvironment. CONCLUSIONS The expression of surfactant metabolism-related genes (SFTPA1, SFTPB, and NAPSA) defines an inflamed subtype of lung adenocarcinoma brain metastases characterized by high abundance of TILs in close vicinity to tumor cells, a prolonged survival, and a tumor microenvironment which might be more accessible to immunotherapeutic approaches.

中文翻译：

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表面活性剂表达定义了与长期存活相关的发炎的肺腺癌脑转移亚型。

目的为了更好地理解免疫系统和脑转移之间的相互作用，从而为这种威胁生命的疾病提供治疗选择。实验设计通过半自动全幻灯片分析对81例肺腺癌的脑转移中的肿瘤浸润淋巴细胞（TIL）进行了定量。多色染色可在单细胞分辨率下对TIL（CD3，CD8和FOXP3）进行表型分析。通过转录组学分析了63例患者中脑转移中TILs程度的分子决定因素。肺腺癌脑转移的发现与已发表的多组原发性肺腺癌有关。《癌症基因组图谱》数据（n = 230）和单细胞RNA测序（scRNA-seq）数据（n = 52,698）。结果肿瘤岛内的TIL数是肺腺癌脑转移患者的独立预后指标。比较转录组学显示，三个表面活性剂代谢相关基因（SFTPA1，SFTPB和NAPSA）的表达与TIL数量密切相关。它们的表达不仅在脑转移中预后，而且在原发性肺腺癌中也有预后。与scRNA-seq数据的相关性表明，表面活性剂基因高表达的脑转移可能起源于类似于2型肺泡细胞的肿瘤细胞。基于甲基蛋白质组的原发性肺腺癌中免疫细胞组分的估计证实了淋巴细胞浸润和表面活性剂表达之间的正相关。具有高表面活性剂表达的肿瘤表现出炎性微环境的转录组谱。结论表面活性物质代谢相关基因（SFTPA1，SFTPB和NAPSA）的表达定义了一种肺腺癌脑转移的发炎亚型，其特征是肿瘤细胞附近TIL的丰度高，存活时间延长和可能存在的肿瘤微环境更容易接受免疫治疗方法。