Surfactant expression defines an inflamed subtype of lung adenocarcinoma brain metastases that correlates with prolonged survival.

Purpose: To provide a better understanding of the interplay between the immune system and brain metastases (BMs) to advance therapeutic options for this life-threatening disease. Experimental Design: Tumor-infiltrating lymphocytes (TILs) were quantified by semi-automated whole slide analysis in BMs from 81 lung adenocarcinomas (LUAD). Multi-color staining enabled phenotyping of TILs (CD3, CD8, and FOXP3) on a single cell resolution. Molecular determinants of the extent of TILs in BMs were analyzed by transcriptomics in a subset of 63 patients. Findings in LUAD BMs were related to published multi-omic primary LUAD TCGA data (n=230) and single-cell RNA-seq (scRNA-seq) data (n=52,698). Results: TIL numbers within tumor islands was an independent prognostic marker in patients with LUAD BMs. 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 BM but also in primary LUADs. 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 LUAD confirmed a positive association between lymphocyte infiltration and surfactant expression. Tumors with a high surfactant expression displayed a transcriptomic profile of an inflammatory microenvironment. Conclusion: The expression of surfactant metabolism-related genes (SFTPA1, SFTPB, 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.