BSBM-15 SYSTEMIC AND LOCAL IMMUNE RESPONSES FOLLOWING STEREOTACTIC RADIOSURGERY TO BRAIN METASTASES FROM HER2-AMPLIFIED BREAST CANCER

BACKGROUND: Brain metastases (BMs) afflict 30-50% of HER2-amplified breast cancer (HER2-BC) patients. Stereotactic radiosurgery (SRS) is a highly effective focal treatment for BMs. Extracranial radiotherapy can promote anti-tumor immune responses that synergize with immunotherapy, but whether this applies to the brain microenvironment remains unclear. Here, we examined blood and BM samples from HER2-BC patients in the TROG 16.02 translational sub-study for immunological effects of SRS (ACTRN12616001265460). METHODS: Blood samples from 10 patients taken pre- and 7-14 days post-SRS to intact HER2-BC BMs or post-resection BM cavities were analyzed by mass and flow cytometry for immune cell and cytokine modulation. One patient received pre-operative SRS for a BM that recurred 6 months after resection, followed by re-resection of the BM 7 days post-SRS. Tumors from pre- and post-SRS timepoints in this patient were analyzed by bulk RNAseq and immunohistochemistry. RESULTS: Monocytes, CD8+ T effector memory and regulatory T cells were enriched in blood post-SRS, while conventional dendritic cells, CD4+ T early and CD4+ TEMRA cells were diminished. Stem cell factor (SCF) concentration, a growth factor important for monocyte production, was elevated in plasma post-SRS. In the tumor, SRS upregulated gene signatures for monocyte/macrophage processes (including SCF gene transcript levels), antigen presentation, and T cell activation. Cell type deconvolution from RNAseq suggested an SRS-induced loss of metastatic tumor cells and enrichment of macrophages and CD4+ T cells. Immunohistochemistry corroborated the influx of CD68+ macrophages and CD3+ T cells into tumor and brain regions post-SRS, with spatial co-localization evident between the cell types. Furthermore, the pre-SRS immune-excluded phenotype in tumor regions was no longer observed post-SRS. CONCLUSION: Systemic and local immunological changes in this homogenous patient cohort receiving SRS to HER2-BC BMs suggest a radiation-induced adaptive immune response intracranially, involving the monocyte-macrophage lineage as antigen presenting cells, that should be further explored.