Estrogen receptor beta signaling in CD8+ T cells boosts T cell receptor activation and antitumor immunity through a phosphotyrosine switch

BackgroundThe non-overlapping functions of the two estrogen receptor subtypes, ERα (Estrogen Receptor α)and ERβ (Estrogen Receptor β), in tumor cells have been studied extensively. However, their counterparts in host cells is vastly underinterrogated. Even less is known about how ERα and ERβ activit...

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Autores principales:	Jing Yang, Rong Li, Bin Yuan, Curtis A Clark, Bogang Wu, Justin M Drerup, Tianbao Li, Victor X Jin, Yanfen Hu, Tyler J Curiel
Formato:	article
Lenguaje:	EN
Publicado:	BMJ Publishing Group 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/9a99bc7f4fa646ec8701df65ded1023e
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spelling	oai:doaj.org-article:9a99bc7f4fa646ec8701df65ded1023e2021-11-16T08:00:04ZEstrogen receptor beta signaling in CD8+ T cells boosts T cell receptor activation and antitumor immunity through a phosphotyrosine switch10.1136/jitc-2020-0019322051-1426https://doaj.org/article/9a99bc7f4fa646ec8701df65ded1023e2021-01-01T00:00:00Zhttps://jitc.bmj.com/content/9/1/e001932.fullhttps://doaj.org/toc/2051-1426BackgroundThe non-overlapping functions of the two estrogen receptor subtypes, ERα (Estrogen Receptor α)and ERβ (Estrogen Receptor β), in tumor cells have been studied extensively. However, their counterparts in host cells is vastly underinterrogated. Even less is known about how ERα and ERβ activities are regulated in a subtype-specific manner. We previously identified a phosphotyrosine residue (pY36) of human ERβ that is important for tumor ERβ to inhibit growth of breast cancer cells in vitro and in vivo. A role of this ERβ phosphotyrosine switch in regulating host ERβ remains unclear.Conventional gene editing was used to mutate the corresponding tyrosine residue of endogenous mouse ERβ (Y55F) in mouse embryonic stem cells. The derived homozygous mutant Esr2Y55F/Y55F mouse strain and its wild-type (WT) counterpart were compared in various transplant tumor models for their ability to support tumor growth. In addition, flow cytometry-based immunophenotyping was carried out to assess antitumor immunity of WT and mutant hosts. Adoptive transfer of bone marrow and purified CD8+ T cells were performed to identify the host cell type that harbors ERβ-dependent antitumor function. Furthermore, cell signaling assays were conducted to compare T cell receptor (TCR)-initiated signaling cascade in CD8+ T cells of WT and mutant mice. Lastly, the ERβ-selective agonist S-equol was evaluated for its efficacy to boost immune checkpoint blockade (ICB)-based anticancer immunotherapy.Disabling the ERβ-specific phosphotyrosine switch in tumor-bearing hosts exacerbates tumor growth. Further, a cell-autonomous ERβ function was defined in CD8+ effector T cells. Mechanistically, TCR activation triggers ERβ phosphorylation, which in turn augments the downstream TCR signaling cascade via a non-genomic action of ERβ. S-equol facilitates TCR activation that stimulates the ERβ phosphotyrosine switch and boosts anti-PD-1 (Programmed cell death protein 1) ICB immunotherapy.Our mouse genetic study clearly demonstrates a role of the ERβ phosphotyrosine switch in regulating ERβ-dependent antitumor immunity in CD8+ T cells. Our findings support the development of ERβ agonists including S-equol in combination with ICB immunotherapy for cancer treatment.Jing YangRong LiBin YuanCurtis A ClarkBogang WuJustin M DrerupTianbao LiVictor X JinYanfen HuTyler J CurielBMJ Publishing GrouparticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENJournal for ImmunoTherapy of Cancer, Vol 9, Iss 1 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Jing Yang Rong Li Bin Yuan Curtis A Clark Bogang Wu Justin M Drerup Tianbao Li Victor X Jin Yanfen Hu Tyler J Curiel Estrogen receptor beta signaling in CD8+ T cells boosts T cell receptor activation and antitumor immunity through a phosphotyrosine switch
description	BackgroundThe non-overlapping functions of the two estrogen receptor subtypes, ERα (Estrogen Receptor α)and ERβ (Estrogen Receptor β), in tumor cells have been studied extensively. However, their counterparts in host cells is vastly underinterrogated. Even less is known about how ERα and ERβ activities are regulated in a subtype-specific manner. We previously identified a phosphotyrosine residue (pY36) of human ERβ that is important for tumor ERβ to inhibit growth of breast cancer cells in vitro and in vivo. A role of this ERβ phosphotyrosine switch in regulating host ERβ remains unclear.Conventional gene editing was used to mutate the corresponding tyrosine residue of endogenous mouse ERβ (Y55F) in mouse embryonic stem cells. The derived homozygous mutant Esr2Y55F/Y55F mouse strain and its wild-type (WT) counterpart were compared in various transplant tumor models for their ability to support tumor growth. In addition, flow cytometry-based immunophenotyping was carried out to assess antitumor immunity of WT and mutant hosts. Adoptive transfer of bone marrow and purified CD8+ T cells were performed to identify the host cell type that harbors ERβ-dependent antitumor function. Furthermore, cell signaling assays were conducted to compare T cell receptor (TCR)-initiated signaling cascade in CD8+ T cells of WT and mutant mice. Lastly, the ERβ-selective agonist S-equol was evaluated for its efficacy to boost immune checkpoint blockade (ICB)-based anticancer immunotherapy.Disabling the ERβ-specific phosphotyrosine switch in tumor-bearing hosts exacerbates tumor growth. Further, a cell-autonomous ERβ function was defined in CD8+ effector T cells. Mechanistically, TCR activation triggers ERβ phosphorylation, which in turn augments the downstream TCR signaling cascade via a non-genomic action of ERβ. S-equol facilitates TCR activation that stimulates the ERβ phosphotyrosine switch and boosts anti-PD-1 (Programmed cell death protein 1) ICB immunotherapy.Our mouse genetic study clearly demonstrates a role of the ERβ phosphotyrosine switch in regulating ERβ-dependent antitumor immunity in CD8+ T cells. Our findings support the development of ERβ agonists including S-equol in combination with ICB immunotherapy for cancer treatment.
format	article
author	Jing Yang Rong Li Bin Yuan Curtis A Clark Bogang Wu Justin M Drerup Tianbao Li Victor X Jin Yanfen Hu Tyler J Curiel
author_facet	Jing Yang Rong Li Bin Yuan Curtis A Clark Bogang Wu Justin M Drerup Tianbao Li Victor X Jin Yanfen Hu Tyler J Curiel
author_sort	Jing Yang
title	Estrogen receptor beta signaling in CD8+ T cells boosts T cell receptor activation and antitumor immunity through a phosphotyrosine switch
title_short	Estrogen receptor beta signaling in CD8+ T cells boosts T cell receptor activation and antitumor immunity through a phosphotyrosine switch
title_full	Estrogen receptor beta signaling in CD8+ T cells boosts T cell receptor activation and antitumor immunity through a phosphotyrosine switch
title_fullStr	Estrogen receptor beta signaling in CD8+ T cells boosts T cell receptor activation and antitumor immunity through a phosphotyrosine switch
title_full_unstemmed	Estrogen receptor beta signaling in CD8+ T cells boosts T cell receptor activation and antitumor immunity through a phosphotyrosine switch
title_sort	estrogen receptor beta signaling in cd8+ t cells boosts t cell receptor activation and antitumor immunity through a phosphotyrosine switch
publisher	BMJ Publishing Group
publishDate	2021
url	https://doaj.org/article/9a99bc7f4fa646ec8701df65ded1023e
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Estrogen receptor beta signaling in CD8+ T cells boosts T cell receptor activation and antitumor immunity through a phosphotyrosine switch

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