Suppressed immune microenvironment and repertoire in brain metastases from patients with resected non-small cell lung cancer.

BACKGROUND The tumor immune microenvironment (TIME) of lung cancer brain metastasis is largely unexplored. We performed immune profiling and sequencing analysis of paired resected primary tumors and brain metastases of non-small cell lung carcinoma (NSCLC). PATIENTS AND METHODS TIME profiling of archival formalin-fixed and paraffin embedded specimens of paired primary tumors and brain metastases from 39 patients with surgically resected NSCLCs was performed using a 770 immune gene expression panel and by T cell receptor beta repertoire (TCRß) sequencing. Immunohistochemistry was performed for validation. Targeted sequencing was performed to catalog hot spot mutations in cancer genes. RESULTS Somatic hot spot mutations were mostly shared between both tumor sites (28/39 patients; 71%). We identified 161 differentially expressed genes, indicating inhibition of dendritic cell maturation, Th1, and leukocyte extravasation signaling pathways, in brain metastases compared to primary tumors (p < 0.01). The proinflammatory cell adhesion molecule vascular cell adhesion protein 1 was significantly suppressed in brain metastases compared to primary tumors. Brain metastases exhibited lower T cell and elevated macrophage infiltration compared with primary tumors (p < 0.001). T cell clones were expanded in 64% of brain metastases compared with their corresponding primary tumors. Further, while TCR repertoires were largely shared between paired brain metastases and primary tumors, T cell densities were sparse in the metastases. CONCLUSION We present findings that suggest that the TIME in brain metastases from NSCLC is immunosuppressed and comprises immune phenotypes (e.g. immunosuppressive tumor-associated macrophages) that may help guide immunotherapeutic strategies for NSCLC brain metastases.