
==== Front
Neurooncol Adv
Neurooncol Adv
noa
Neuro-Oncology Advances
2632-2498
Oxford University Press US

10.1093/noajnl/vdae090.135
vdae090.135
Final Category: Translational Science
AcademicSubjects/MED00300
AcademicSubjects/MED00310
TRSC-07 COMBINATION OF ENDOCRINE THERAPY WITH RADIATION DECREASES BRAIN METASTASES THROUGH REACTIVATION OF EFFECTOR IMMUNE-CELL RECRUITMENT TO THE BRAIN
Contreras-Zarate Maria Jose University of Colorado AMC, Aurora, USA

Alvarez-Eraso Karen University of Colorado AMC, Aurora, USA

Goodspeed Andrew University of Colorado AMC, Aurora, USA

Costello James University of Colorado AMC, Aurora, USA

Jaramillo-Gomez Jenny University of Colorado AMC, Aurora, USA

Koliavas Stella University of Colorado AMC, Aurora, USA

Fox Morgan University of Colorado AMC, Aurora, USA

Ormond Ryan University of Colorado AMC, Aurora, USA

Kabos Peter University of Colorado AMC, Aurora, USA

Karam Sana University of Colorado AMC, Aurora, USA

Cittelly Diana University of Colorado AMC, Aurora, USA

8 2024
02 8 2024
02 8 2024
6 Suppl 1 2024 SNO/ASCO CNS Metastases Conference i41i41
© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

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.
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pmc
