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Blocking of oestrogen signals improves anti-tumour effect regardless of oestrogen receptor alpha expression in cancer cells

British Journal of Cancer volume 129, pages 935–946 (2023)Cite this article

Subjects

Abstract

Background

Anti-oestrogenic therapy has been used for breast cancer patients with oestrogen susceptibility cancer cells. However, little has been known about its potential role for immune cell biology within TME, particularly in cancer patients without oestrogen sensitivity of tumour cells. Therefore, we aimed to study the effect of oestrogen on immunity within TME.

Methods

Using a clinical dataset, immune cells of humans and mice, female mice with and without ovaries, and several murine ERα-negative cancer cell lines, we evaluated the effect of oestrogen on immunity in TME.

Results

Clinical data analysis suggested oestrogen’s suppressive efficacy against CTLs. Additionally, in vitro and in vivo experiments revealed intra-tumoural CTLs’ direct repressive action by oestrogen in both mice and humans; blockade of oestrogen signals cancelled its immunosuppression resulting in tumour growth reduction in vivo. Most notably, immunotherapy (immune checkpoint inhibitor; ICI) combined with anti-oestrogenic therapy exhibited a dramatic anti-tumour effect.

Conclusions

This study provides novel insights into how oestrogen contributes to tumour progression and a therapeutic rationale for blocking oestrogen signalling to boost the anti-tumour effect of ICI, regardless of tumour cells’ ERα expression.

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Fig. 1: Potential involvement of oestrogen-inducible enzyme HSD17B1 with immunity in human TNBC.
Fig. 2: Effects of oestrogen on tumour growth and survival in ERα-negative cancers.
Fig. 3: Effects of ER antagonist (fulvestrant) on ERα-negative tumour growth and tumour microenvironment.
Fig. 4: CD8+ T cell-mediated mechanisms of anti-tumour effect by ER antagonist in ERα-negative cancer.
Fig. 5: Effects of ER antagonist combined with immune checkpoint inhibitor on ERα-negative tumour growth.
Fig. 6: Effects of fulvestrant combined with immune checkpoint inhibitors and chemotherapy on ERα-negative tumour growth.

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Data availability

Data are available on reasonable request. The datasets used and/or analysed during the current study are available from the corresponding author.

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Acknowledgements

The authors thank Tomoki Murata, Masafumi Tanji, Nanumi Han, Haruka Wada, and Yoshinori Hasegawa for their helpful discussions and advice, and technical assistance with part of some experiments.

Funding

This work was partly supported by JST SPRING (#JPMJSP2119, NK) and JSPS KAKENHI (#22J21076, NK).

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Authors and Affiliations

  1. Division of Immunobiology, Graduate School of Medicine, Institute for Genetic Medicine, Hokkaido University, Kita-15 Nishi-7, Sapporo, 060-0815, Japan

    Nabeel Kajihara, Yunqi Ge & Ken-ichiro Seino

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  1. Nabeel Kajihara
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Contributions

NK and K-iS designed the study. NK and YG performed experiments. All authors analysed data and discussed the results. NK and K-iS contributed to manuscript preparation. All authors approved the final version of this manuscript for publication.

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Correspondence to Ken-ichiro Seino.

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All animal procedures were approved by the Animal Care Committee of Hokkaido University (Approval number: 19-0094).

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Kajihara, N., Ge, Y. & Seino, Ki. Blocking of oestrogen signals improves anti-tumour effect regardless of oestrogen receptor alpha expression in cancer cells. Br J Cancer 129, 935–946 (2023). https://doi.org/10.1038/s41416-023-02381-0

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