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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.

References

  1. Chen C, Gong X, Yang X, Shang X, Du Q, Liao Q, et al. The roles of estrogen and estrogen receptors in gastrointestinal disease (Review). Oncol Lett. 2019;18:5673–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Tohyama S, Ogino Y, Lange A, Myosho T, Kobayashi T, Hirano Y, et al. Establishment of estrogen receptor 1 (ESR1)-knockout medaka: ESR1 is dispensable for sexual development and reproduction in medaka, Oryzias latipes. Dev Growth Differ. 2017;59:552–61.

    Article  CAS  PubMed  Google Scholar 

  3. Gompel A. Hormone and breast cancer. Presse Medicale. 2019;48:1085–91.

    Article  PubMed  Google Scholar 

  4. Lin CY, Ström A, Vega VB, Kong SL, Yeo AL, Thomsen JS, et al. Discovery of estrogen receptor alpha target genes and response elements in breast tumor cells. Genome Biol. 2004;5:R66.

  5. Cunningham M, Gilkeson G. Estrogen receptors in immunity and autoimmunity. Clin Rev Allergy Immunol. 2011;40:66–73.

    Article  CAS  PubMed  Google Scholar 

  6. Wang T, Jin J, Qian C, Lou J, Lin J, Xu A, et al. Estrogen/ER in anti-tumor immunity regulation to tumor cell and tumor microenvironment. Cancer Cell Int. 2021;21:1–13.

    Google Scholar 

  7. Chuffa LGdA, Lupi-Júnior LA, Costa AB, Amorim JPdA, Seiva FR. The role of sex hormones and steroid receptors on female reproductive cancers. Steroids. 2017;118:93–108.

    Article  CAS  PubMed  Google Scholar 

  8. Hsieh CC, Trichopoulos D, Katsouyanni K, Yuasa S. Age at menarche, age at menopause, height and obesity as risk factors for breast cancer: Associations and interactions in an international case‐control study. Int J Cancer. 1990;46:796–800.

    Article  CAS  PubMed  Google Scholar 

  9. Zattarin E, Leporati R, Ligorio F, Lobefaro R, Vingiani A, Pruneri G, et al. Hormone receptor loss in breast cancer: molecular mechanisms, clinical settings, and therapeutic implications. Cells. 2020;9:2644.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Morgan DAL, Refalo NA, Cheung KL. Strength of ER-positivity in relation to survival in ER-positive breast cancer treated by adjuvant tamoxifen as sole systemic therapy. Breast. 2011;20:215–9.

    Article  PubMed  Google Scholar 

  11. Braun L, Mietzsch F, Seibold P, Schneeweiss A, Schirmacher P, Chang-Claude J, et al. Intrinsic breast cancer subtypes defined by estrogen receptor signalling-prognostic relevance of progesterone receptor loss. Mod Pathol. 2013;26:1161–71.

    Article  CAS  PubMed  Google Scholar 

  12. Backes FJ, Walker CJ, Goodfellow PJ, Hade EM, Agarwal G, Mutch D, et al. Estrogen receptor-alpha as a predictive biomarker in endometrioid endometrial cancer. Gynecol Oncol. 2016;141:312–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Deepak KGK, Vempati R, Nagaraju GP, Dasari VR, Nagini S, Rao DN, et al. Tumor microenvironment: challenges and opportunities in targeting metastasis of triple negative breast cancer. Pharmacol Res. 2020;153:104683.

    Article  CAS  PubMed  Google Scholar 

  14. Kajihara N, Kobayashi T, Otsuka R, Nio J, Tomohiro K. Tumor - derived interleukin-34 creates an immunosuppressive and chemoresistant tumor microenvironment by modulating myeloid-derived suppressor cells in triple-negative breast cancer. Cancer Immunol Immunother. 2023;72:851–64.

    Article  CAS  PubMed  Google Scholar 

  15. Hangai S, Kawamura T, Kimura Y, Chang CY, Hibino S, Yamamoto D, et al. Orchestration of myeloid-derived suppressor cells in the tumor microenvironment by ubiquitous cellular protein TCTP released by tumor cells. Nat Immunol. 2021;22:947–57.

    Article  CAS  PubMed  Google Scholar 

  16. Márquez-Garbán DC, Deng G, Comin-Anduix B, Garcia AJ, Xing Y, Chen HW, et al. Antiestrogens in combination with immune checkpoint inhibitors in breast cancer immunotherapy. J Steroid Biochem Mol Biol. 2019;193:105415.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Chakraborty B, Byemerwa J, Shepherd J, Haines CN, Baldi R, Gong W, et al. Inhibition of estrogen signaling in myeloid cells increases tumor immunity in melanoma. J Clin Investig. 2021;131:1–16.

    Article  Google Scholar 

  18. Salem ML. Estrogen, a double-edged sword: modulation of TH1- and TH2-mediated inflammations by differential regulation of TH1/TH2 cytokine production. Curr Drug Targets Inflamm Allergy. 2004;3:97–104.

    Article  CAS  PubMed  Google Scholar 

  19. Nakamura N, Miyazaki K, Kitano Y, Fujisaki S, Okamura H. Suppression of cytotoxic T-lymphocyte activity during human pregnancy. J Reprod Immunol. 1993;23:119–30.

    Article  CAS  PubMed  Google Scholar 

  20. Haghmorad D, Amini AA, Mahmoudi MB, Rastin M, Hosseini M, Mahmoudi M. Pregnancy level of estrogen attenuates experimental autoimmune encephalomyelitis in both ovariectomized and pregnant C57BL/6 mice through expansion of Treg and Th2 cells. J Neuroimmunol. 2014;277:85–95.

    Article  CAS  PubMed  Google Scholar 

  21. Conforti F, Pala L, Bagnardi V, De Pas T, Martinetti M, Viale G, et al. Cancer immunotherapy efficacy and patients’ sex: a systematic review and meta-analysis. Lancet Oncol. 2018;19:737–46.

    Article  CAS  PubMed  Google Scholar 

  22. Svoronos N, Perales-Puchalt A, Allegrezza MJ, Rutkowski MR, Payne KK, Tesone AJ, et al. Tumor cell–independent estrogen signaling drives disease progression through mobilization of myeloid-derived suppressor cells. Cancer Discov. 2017;7:72–85.

    Article  CAS  PubMed  Google Scholar 

  23. Grumbach MM, Auchus RJ. Estrogen: consequences and implications of human mutations in synthesis and action. J Clin Endocrinol Metab. 1999;84:4677–94.

    CAS  PubMed  Google Scholar 

  24. Wu AH, Seow A, Arakawa K, Van Den Berg D, Lee HP, Yu MC. HSD17B1 and CYP17 polymorphisms and breast cancer risk among Chinese women in Singapore. Int J Cancer. 2003;104:450–7.

    Article  CAS  PubMed  Google Scholar 

  25. Setiawan VW, Hankinson SE, Colditz GA, Hunter DJ, De Vivo I. HSD17B1 gene polymorphisms and risk of endometrial and breast cancer. Cancer Epidemiol Biomarkers Prev. 2004;13:213–9.

    Article  CAS  PubMed  Google Scholar 

  26. Treeck O, Schüler-Toprak S, Ortmann O. Estrogen actions in triple-negative breast cancer. Cells. 2020;9:2358.

  27. Howell SJ, Johnston SRD, Howell A. The use of selective estrogen receptor modulators and selective estrogen receptor down-regulators in breast cancer. Best Pract Res Clin Endocrinol Metab. 2004;18:47–66.

    Article  CAS  PubMed  Google Scholar 

  28. Tang H, Liao Y, Zhang C, Chen G, Xu L, Liu Z, et al. Fulvestrant-mediated inhibition of estrogen receptor signaling slows lung cancer progression. Oncol Res. 2014;22:13–20.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Mishra AK, Abrahamsson A, Dabrosin C. Fulvestrant inhibits growth of triple negative breast cancer and synergizes with tamoxifen in ERα positive breast cancer by up-regulation of ERβ. Oncotarget. 2016;7:56876–88.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Lumachi F, Brunello A, Maruzzo M, Basso U, Basso S. Treatment of estrogen receptor-positive breast cancer. Curr Med Chem. 2013;20:596–604.

    Article  CAS  PubMed  Google Scholar 

  31. Ross SH, Cantrell DA. Signaling and function of interleukin-2 in T lymphocytes. Annu Rev Immunol. 2018;36:411–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Feau S, Arens R, Togher S, Schoenberger SP. Autocrine IL-2 is required for secondary population expansion of CD8 + memory T cells. Nat Immunol. 2011;12:908–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Dai Z, Konieczny BT, Lakkis FG. The dual role of IL-2 in the generation and maintenance of CD8 + memory T cells. J Immunol. 2000;165:3031–6.

    Article  CAS  PubMed  Google Scholar 

  34. Johnston JA, Bacon CM, Finbloom DS, Rees RC, Kaplan D, Shibuya K, et al. Tyrosine phosphorylation and activation of STAT5, STAT3, and Janus kinases by interleukins 2 and 15. Proc Natl Acad Sci USA. 1995;92:8705–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kajihara N, Kitagawa F, Kobayashi T, Wada H, Otsuka R, Seino KI. Interleukin-34 contributes to poor prognosis in triple-negative breast cancer. Breast Cancer. 2020;27:1198–204.

    Article  PubMed  Google Scholar 

  36. Balkwill FR, Capasso M, Hagemann T. The tumor microenvironment at a glance. J Cell Sci. 2012;125:5591–6.

    Article  CAS  PubMed  Google Scholar 

  37. Liu R, Yang F, Yin JY, Liu YZ, Zhang W, Zhou HH. Influence of tumor immune infiltration on immune checkpoint inhibitor therapeutic efficacy: a computational retrospective study. Front Immunol. 2021;12:1–15.

    Google Scholar 

  38. Chapman PB, Jayaprakasam VS, Panageas KS, Callahan M, Postow MA, Shoushtari AN, et al. Risks and benefits of reinduction ipilimumab/nivolumab in melanoma patients previously treated with ipilimumab/nivolumab. J Immunother Cancer. 2021;9:1–6.

    Article  Google Scholar 

  39. Kagihara JA, Andress M, Diamond JR. Nab-paclitaxel and atezolizumab for the treatment of PD-L1-positive, metastatic triple-negative breast cancer: review and future directions. Expert Rev Precis Med Drug Dev. 2020;5:59–65.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Zhao X, Subramanian S. Intrinsic resistance of solid tumors to immune checkpoint blockade therapy. Cancer Res. 2017;77:817–22.

    Article  CAS  PubMed  Google Scholar 

  41. Tie Y, Tang F, Wei YQ, Wei XW. Immunosuppressive cells in cancer: mechanisms and potential therapeutic targets. J Hematol Oncol. 2022;15:61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Guan X, Polesso F, Wang C, Sehrawat A, Hawkins RM, Murray SE, et al. Androgen receptor activity in T cells limits checkpoint blockade efficacy. Nature. 2022;606:791–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Hama N, Kobayashi T, Han N, Kitagawa F, Kajihara N, Otsuka R, et al. Interleukin-34 limits the therapeutic effects of immune checkpoint blockade. iScience. 2020;23:101584.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Sade-Feldman M, Yizhak K, Bjorgaard SL, Ray JP, de Boer CG, Jenkins RW, et al. Defining T cell states associated with response to checkpoint immunotherapy in melanoma. Cell. 2018;175:998.e20–1013.e20.

    Article  Google Scholar 

  45. Boyman O, Sprent J. The role of interleukin-2 during homeostasis and activation of the immune system. Nat Rev Immunol. 2012;12:180–90.

    Article  CAS  PubMed  Google Scholar 

  46. Mitchell DM, Ravkov EV, Williams MA. Distinct roles for IL-2 and IL-15 in the differentiation and survival of CD8+ effector and memory T cells. J Immunol. 2010;184:6719–30.

    Article  CAS  PubMed  Google Scholar 

  47. Cho JH, Boyman O, Kim HO, Hahm B, Rubinstein MP, Ramsey C, et al. An intense form of homeostatic proliferation of naive CD8+ cells driven by IL-2. J Exp Med. 2007;204:1787–801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Sun Z, Ren Z, Yang K, Liu Z, Cao S, Deng S, et al. A next-generation tumor-targeting IL-2 preferentially promotes tumor-infiltrating CD8 + T-cell response and effective tumor control. Nat Commun. 2019;10:3874.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kovats S. Estrogen receptors regulate innate immune cells and signaling pathways. Cell Immunol. 2015;294:63–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Phiel KL, Henderson RA, Adelman SJ, Elloso MM. Differential estrogen receptor gene expression in human peripheral blood mononuclear cell populations. Immunol Lett. 2005;97:107–13.

    Article  CAS  PubMed  Google Scholar 

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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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  2. Yunqi Ge
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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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