TRSC-07 Combination of Endocrine Therapy With Radiation Decreases Brain Metastases Through Reactivation of Effector Immune-Cell Recruitment to the Brain

Abstract Younger women with breast cancer have increased risk of development of brain metastases (BM) irrespective of the tumor subtype. We have shown that pre-menopausal levels of 17-β-Estradiol (E2) promotes BM of estrogen receptor negative (ER¯) BC cells by inducing neuroinflammatory ER+ glial cells to secrete pro-metastatic factors critical for early brain colonization. Yet, the clinical translation of endocrine therapies (ET) to the management of BM requires a better understanding of its effectiveness at late stages of metastatic progression and its interactions with current standard of care (SOC). Using scRNAseq of brain immune cells isolated from E2 or E2-suppressed mice carrying BMs we show that pre-menopausal levels of E2 suppressed immune surveillance, activation, and IRF-7/interferon-driven anti-tumoral programs in microglia. Multiparametric flow cytometry show that E2 repressed recruitment of T, B and NK cells to the brain niche from early to late stages of BM progression and ET (ovarian suppression and aromatase inhibitors) restored recruitment of these effector immune cells to the brain. ET decreased BM progression when used in combination with brain radiotherapy (RT), but not when ET was used alone or in immunocompromised mouse models, suggesting ET-induced recruitment of interferon driven T, B and NK cells to the brain synergizes with radiotherapy to promote more effective anti-tumoral immune responses. Depletion of CD4+T, CD8+T, and NK1.1+ cells in E2-suppressed mice carrying BMs showed that anti-tumoral effects of RT and ET depend on CD4T and NK cells. Suppression of CD4+ T cells further increased the effectiveness of ET and RT and improved survival, suggesting that subsets of T cells, possibly Treg cells are critical to regulate BM antitumoral responses. While ET+RT were comparable to anti-PD-1+RT in decreasing BMs, their effects were not additive. Thus, our results suggest that FDA-approved ET synergizes with RT but not PD-1 inhibitors for treatment of BMs.