@article{d1c5d5caa63c4361bf4046d30b8bf7d0,
title = "Pharmacological Activation of Estrogen Receptor Beta Overcomes Tumor Resistance to Immune Checkpoint Blockade Therapy",
abstract = "The emerging immune checkpoint blockade (ICB) therapy has ushered the cancer therapeutics field into an era of immunotherapy. Although ICB treatment provides remarkable clinical responses in a subset of patients with cancer, this regimen fails to extend survival in a large proportion of patients. Here, we found that a combined treatment of estrogen receptor beta (ERβ) agonist and PD-1 antibody treatment improved therapeutic efficacy in mouse tumor models, compared with monotherapies, by reducing infiltration of myeloid-derived suppressor cells (MDSCs) and increasing CD8+ T cells in tumors. Mechanistically, LY500307 treatment reduced tumor-derived CSF1 and decreased infiltration of CSF1R+ MDSCs in the tumor bed. CSF1 released by tumor cells induced CSF1R+ MDSC chemotaxis in vitro and blockade of CSF1R demonstrated similar therapeutic effects as ERβ activation in vivo. Collectively, our study proved combined treatment of ERβ agonist and PD-1 antibody reduced MDSC infiltration in the tumor and enhanced tumor response to ICB therapy.",
keywords = "Cancer, Endocrine Treatment, Immunology",
author = "Shuang Huang and Nianxin Zhou and Linjie Zhao and Gimple, {Ryan C.} and Ahn, {Young Ha} and Peidong Zhang and Wei Wang and Bin Shao and Jingyun Yang and Qian Zhang and Sai Zhao and Xuehan Jiang and Zhiwei Chen and Yangfan Zeng and Hongbo Hu and Gustafsson, {Jan {\AA}ke} and Shengtao Zhou",
note = "Funding Information: This work was supported by grants from National Natural Science Foundation of China (grant #81822034, grant # 81821002, and grant #81773119), National Key Research and Development Program of China (grant #2018YFA0109200 and grant #2017YFA0106800), Sichuan Science-Technology International Cooperation Project (grant #2019YFH0144), Direct Scientific Research Grants from West China Second Hospital, Sichuan University (grant #KS021, grant #K1907, and grant KX247), the Robert A Welch Foundation for a grant (grant #E-0004), the Swedish Cancer Foundation, the Center for Innovative Medicine and the Novo Nordisk Fund. Conceptualization, H.H. J.-A.G. and S.Z.; Methodology, S.H. N.Z. J.-A.G. and S.Z.; Investigation, S.H. N.Z. B.S. J.Y. Q.Z. S.Z. X.J. Z.C. P.Z. and Y.Z.; Formal analysis, W.W. L.Z. R.C.G. J.-A.G. and S.Z.; Writing ? Original Draft, S.H. N.Z. J.-A.G. and S.Z.; Writing ? Review and Editing, L.Z. R.C.G. Y.H.A. H.H. J.-A.G. and S.Z.; Supervision, H.H. J.-A.G. and S.Z.; Funding Acquisition, H.H. J.-A.G. and S.Z. No competing interests were declared. Funding Information: This work was supported by grants from National Natural Science Foundation of China (grant #81822034 , grant # 81821002 , and grant #81773119 ), National Key Research and Development Program of China (grant #2018YFA0109200 and grant #2017YFA0106800 ), Sichuan Science-Technology International Cooperation Project (grant #2019YFH0144 ), Direct Scientific Research Grants from West China Second Hospital , Sichuan University (grant #KS021 , grant #K1907 , and grant KX247 ), the Robert A Welch Foundation for a grant (grant #E-0004 ), the Swedish Cancer Foundation , the Center for Innovative Medicine and the Novo Nordisk Fund . Publisher Copyright: {\textcopyright} 2020 The Author(s) Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",
year = "2020",
month = sep,
day = "25",
doi = "10.1016/j.isci.2020.101458",
language = "English (US)",
volume = "23",
journal = "iScience",
issn = "2589-0042",
number = "9",
}