| First Author | Yuan B | Year | 2021 |
| Journal | J Immunother Cancer | Volume | 9 |
| Issue | 1 | PubMed ID | 33462142 |
| Mgi Jnum | J:308292 | Mgi Id | MGI:6728630 |
| Doi | 10.1136/jitc-2020-001932 | Citation | Yuan B, et al. (2021) Estrogen receptor beta signaling in CD8(+) T cells boosts T cell receptor activation and antitumor immunity through a phosphotyrosine switch. J Immunother Cancer 9(1) |
| abstractText | BackgroundThe non-overlapping functions of the two estrogen receptor subtypes, ERalpha (Estrogen Receptor alpha)and ERbeta (Estrogen Receptor beta), in tumor cells have been studied extensively. However, their counterparts in host cells is vastly underinterrogated. Even less is known about how ERalpha and ERbeta activities are regulated in a subtype-specific manner. We previously identified a phosphotyrosine residue (pY36) of human ERbeta that is important for tumor ERbeta to inhibit growth of breast cancer cells in vitro and in vivo. A role of this ERbeta phosphotyrosine switch in regulating host ERbeta remains unclear.Conventional gene editing was used to mutate the corresponding tyrosine residue of endogenous mouse ERbeta (Y55F) in mouse embryonic stem cells. The derived homozygous mutant Esr2(Y55F/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 ERbeta-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 ERbeta-selective agonist S-equol was evaluated for its efficacy to boost immune checkpoint blockade (ICB)-based anticancer immunotherapy.Disabling the ERbeta-specific phosphotyrosine switch in tumor-bearing hosts exacerbates tumor growth. Further, a cell-autonomous ERbeta function was defined in CD8(+) effector T cells. Mechanistically, TCR activation triggers ERbeta phosphorylation, which in turn augments the downstream TCR signaling cascade via a non-genomic action of ERbeta. S-equol facilitates TCR activation that stimulates the ERbeta phosphotyrosine switch and boosts anti-PD-1 (Programmed cell death protein 1) ICB immunotherapy.Our mouse genetic study clearly demonstrates a role of the ERbeta phosphotyrosine switch in regulating ERbeta-dependent antitumor immunity in CD8(+) T cells. Our findings support the development of ERbeta agonists including S-equol in combination with ICB immunotherapy for cancer treatment. |
