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

Abstract

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.

An analysis of sexual dimorphism in the tumor microenvironment of colorectal cancer

“…In addition, a decreased incidence of CRC was seen in postmenopausal women taking combined estrogen and progesterone compared to those not on hormone therapy (14, 15). Similarly, the mechanistic role of E2 and ESR2 in providing survival advantage in women with CRC has been demonstrated (16)(17)(18). However, it is unclear what role female sex hormones have in men with regards to tumor development, and the inconsistency of hormonal influences on incidence and survival in men with CRC suggests mechanisms of survival beyond hormonal effects on the tumors (19).…”

Foods may modify responsiveness to cancer immune checkpoint blockers by altering both the gut microbiota and activation of estrogen receptors in immune cells

“…Further, ERb agonists reduced tumor MDSC infiltration and enhanced tumor response to ICB therapy (Huang et al, 2020). ERb knockout mice also exhibited impaired antitumor immunity (Yuan et al, 2021). These results suggest that estrogenic compounds which preferentially activate ERb or GPER might improve ICB responsiveness in cancer patients.…”

“…It is also preferentially activated by phytoestrogens (Du et al, 2018;Calfio et al, 2021;Li et al, 2022). In immune cells, activation of ERb (Zhao et al, 2018;Yuan et al, 2021) and GPER (Natale et al, 2018) can activate CD8+ T cells. In turn, the activation of T cell receptor (TCR) signaling in CD8+ T cells triggers ERb phosphorylation to further promote TCR signaling cascade and the effectiveness of ICB immunotherapy (Yuan et al, 2021).…”

“…In immune cells, activation of ERb (Zhao et al, 2018;Yuan et al, 2021) and GPER (Natale et al, 2018) can activate CD8+ T cells. In turn, the activation of T cell receptor (TCR) signaling in CD8+ T cells triggers ERb phosphorylation to further promote TCR signaling cascade and the effectiveness of ICB immunotherapy (Yuan et al, 2021). Further, ERb agonists reduced tumor MDSC infiltration and enhanced tumor response to ICB therapy (Huang et al, 2020).…”

Genomic variation, origin tracing, and vaccine development of SARS-CoV-2: A systematic review

“…The timeline of progression of SARS-CoV-2 vaccine development is shown in Figure 4. The WHO COVID-19 vaccine progress draft shows that 173 prospective vaccines for COVID-19 are currently in the preclinical stage as of January 2021, 92,93 while 64 candidate vaccines have entered clinical trials, 22 of which are in phase II/III or phase III clinical trials. The traditional strategy for development of coronavirus vaccines relies on virus inactivation, virus attenuation, and recombinant protein methods.…”