Oestradiol represses anti-tumoural immune response to promote progression of brain metastases

Oestradiol promotes brain metastatic progression by stimulating an immunosuppressive brain microenvironment, results from a preclinical study showed. Therefore, oestrogen-depletion therapies could be used in combination with brain irradiation to promote a more effective anti-tumoural immune response.

Young age (<45 years) is a significant and independent predictor for the development of brain metastases in breast cancer, irrespective of the tumour subtype. In addition, the incidence of brain metastasis is higher in pre-menopausal women compared with post-menopausal women (53% vs 25%) [1]. Previously, it was shown that pre-menopausal levels of 17-β oestradiol (E2) promote brain metastasis of ER-negative breast cancer cells by inducing the secretion of pro-metastatic factors critical for early brain colonisation [2]. Ovariectomy in combination with the aromatase inhibitor letrozole prevented brain colonisation of TNBC human xenografts and murine models through paracrine activation of EGFR and TrkB, pathways involved in increased invasion and early tumour initiation [2].

Yet, it remains unknown to what extent E2-depleting therapies can decrease progression of established brain metastases in combination with current standard-of-care for brain metastasis (irradiation and immunotherapy). A study in mice was performed to assess how E2-depleting therapies alone or in combination with standard-of-care decrease the progression of existing brain metastases in TNBC. Dr Maria Contreras-Zarate (University of Colorado, CO, USA) presented the results [3].

The results showed that E2-withdrawal in combination with letrozole and radiation decreased brain metastatic burden significantly as compared with E2-treated mice, but not without radiation, suggesting that the effectiveness of E2 suppression to decrease progression of existing metastasis depends on the priming of the immune system by radiation. In line with this, no effects of E2 withdrawal in combination with letrozole and irradiation were observed in immunodeficient (NGS) mice. In addition, it was shown that E2 suppression activates immune-surveillance at early stages of brain colonisation and recruits T and B cells to the brain at later stages of metastatic progression.

“Our results support the hypothesis that oestradiol promotes brain metastatic progression by stimulating an immunosuppressive brain microenvironment,” Dr Contreras-Zarate concluded. “Therefore, E2-depleting therapies like aromatase inhibitors and selective oestrogen modulators could be used in combination with brain irradiation to promote a more effective anti-tumoural immune response.”

1. Hung MH, et al. PLoS ONE. 2014;9:e89389.
2. Contreras-Zarate MJ, et al. 2019;38:4685–4699.
3. Contreras-Zarate MJ, et al. Estradiol represses anti-tumoral immune response to promote progression of ER¯ brain metastases. Abstract GS5-07, SABCS 2022, 6–10 December, San Antonio, TX, USA.

Copyright ©2023 Medicom Medical Publishers



Posted on 1 February 202325 March 2024