Ionizing Radiation Enhances Prognostically Significant Cellular Immunity Programs in the Brain Metastasis...

Brain metastasis (BM) is a deadly complication of systemic malignancy that has been associated with defective cellular immunity. We sought to characterize the foundational elements and clinical relevance of BM-associated immunosuppression using integrated molecular profiling in primary patient material.

Retrospective patient tissue cohorts of breast (n = 153) and lung (n = 153) cancer BM were stratified by histopathologic scoring of tumor-infiltrating lymphocytes (TIL) and clinical outcome, with a large subset of breast cancer samples further analyzed by T-cell receptor sequencing (TCR-seq) and RNA sequencing (RNA-seq). An ongoing clinical trial comparing pre- and postoperative stereotactic radiosurgery (SRS)/stereotactic radiotherapy (SRT) in BM management was then leveraged to dissect radiation-induced immune responses by TCR- and RNA-seq.

Patients with high-grade histopathologic TIL infiltration and enriched TCR diversity demonstrated favorable prognoses in breast and lung cancer BM. Moreover, SRS/SRT treatment enhanced TCR diversity in the BM microenvironment, along with signatures of antigen processing and presentation. Finally, integrated analysis demonstrated that IR seemed to reactivate immune microenvironmental signatures normally suppressed in BM and upregulate immune signaling pathways correlated with favorable outcomes in patients with breast cancer BM.

High TCR diversity in BM is associated with improved prognosis and highlights therapeutically tractable targets within the immune microenvironment. Moreover, we show in a prospective clinical trial that IR enhances T-cell-mediated immune responses, upregulating antigen presentation and enhancing TCR diversity in BM. These results argue for increased therapeutic investigations of radiation-induced immunomodulatory effects in BM, potentially in association with immune checkpoint inhibition.