BSCI-18 ESTROGEN-DEPLETION DECREASES PROGRESSION OF ER¯ BRAIN METASTASES BY PROMOTING AN ANTI-TUMORAL LOCAL IMMUNE RESPONSE. (5th August 2022)

• Record Type: Journal Article
• Authors: Contreras-Zarate, Maria; Alvarez-Eraso, Karen; Littrell, Zachary; Tsuji, Nicole; Karam, Sana; Ormond, D Ryan; Kabos, Peter; Cittelly, Diana
• Is Part Of: Neuro-oncology advances. Volume 4(2022)Supplement 1
• Page Start: i4
• Page End: i4
• Publication Date: 2022-08-05
• Subjects: 616.99481
• DOI: 10.1093/noajnl/vdac078.016
• Languages: English
• ISSNs: 2632-2498

Abstract

Abstract: We have shown that 17-β-Estradiol (E2) promotes brain metastasis (BM) of estrogen receptor negative (ER¯) BC cells by inducing neuroinflammatory ER+ astrocytes in the brain niche to secrete pro-metastatic factors critical for early brain colonization. E2-depletion prevented brain colonization of human xenografts (MDA231BR/NSG) and syngeneic (E0711/C57Bl6, 4T1/Balb-c) ER¯ models. Yet, whether E2-depletion can be used to decrease progression of established BM and how E2-dependent modulation of brain immune response contributes to the pro-metastatic effects of E2 remains unclear. To assess whether E2-depletion could decrease BM progression in a model that mimics standard of care for BM, E0771-GFP-luc cells were injected intracardially in syngeneic ovariectomized (OVX)-female C57Bl6 mice supplemented with E2. Seven days after injection (when micrometastases are established), mice received a single 15Gy dose brain irradiation and were randomized to continue receiving E2, E2 withdrawal (E2WD) or E2WD plus the aromatase-inhibitor letrozole (EWD+LET). Endpoint BM (but not systemic metastases) were significantly decreased in E2WD+Letrozole treated mice as compared to E2-treated mice. This effect was abolished when E0711 cells were injected in severely immunocompromised NSG mice or in the absence of brain irradiation, suggesting EWD+LET decreases BM progression through boosting radiation-induced anti-tumor immunity. Accordingly, there were no differences in BM progression in E2, EWD or E2WD+let treated mice in a xenograft model (F2-7 TNBC cells) in NSG mice, even in the presence of brain irradiation. Brain immune-profiling of brain irradiated E2, EWD and EWD+Let C57BL6 mice carrying E0771 BMs shows that brains of EWD+LET-treated mice had a significantly lower fraction of CD4 T cells and an increase in CD8 T cells, suggesting that EWD+letrozole decrease brain metastatic burden in part through modulation of T cells. These results suggest E2-depletion therapies could be used in combination with brain irradiation to decrease progression of BMs and promote an anti-tumoral immune response.