Osteogenesis and Antibacterial Activity of Graphene Oxide and Dexamethasone Coatings on Porous Polyetheretherketone via Polydopamine-Assisted Chemistry

Endowing implants with antibacterial ability and osteogenic ability plays important roles in preventing post-operative bacterial contamination and facilitating integration between implants and osseous tissue, consequently reducing implant failure rates. In this study, we develop a facile and versatile strategy with dopamine as an auxiliary for construction of dexamethasone (Dex)/liposome porous coatings. In detail, the surfaces of sulfonated polyetheretherketone (SP) plates are coated with polydopamine firstly and then modified with graphene oxide (GO) and dexamethasone (Dex)-loaded liposome, which is verified by contact angle, X-ray photoelectron spectroscopy (XPS), attenuated total reflection infrared (ATR), and Raman spectra. The results of our study suggest that the GO and Dex are successfully coated on the samples’ surfaces. In vitro cell attachment, growth, differentiation, and apatite deposition tests all illustrate that the substrate coated with GO and Dex can significantly accelerate the proliferation and osteogenic differentiation of MC3T3 cells compared with the pristine sulfonated polyetheretherketone (PEEK). Additionally, it exhibits acceptable antibacterial activity against E. coli and S. aureus in vitro. Altogether, our results demonstrate that the modified GO- and Dex-loaded substrates are endowed with impressive biocompatibility and certain antibacterial qualities, making it possible for future application as a perspective implant material

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 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

Adipose PD-L1 Modulates PD-1/PD-L1 Checkpoint Blockade Immunotherapy Efficacy in Breast Cancer.

Programmed death-ligand 1 (PD-L1) and its receptor programmed cell death protein 1 (PD-1) modulate antitumor immunity and are major targets of checkpoint blockade immunotherapy. However, clinical trials of anti-PD-L1 and anti-PD-1 antibodies in breast cancer demonstrate only modest efficacy. Furthermore, specific PD-L1 contributions in various tissue and cell compartments to antitumor immunity remain incompletely elucidated. Here we show that PD-L1 expression is markedly elevated in mature adipocytes versus preadipocytes. Adipocyte PD-L1 prevents anti-PD-L1 antibody from activating important antitumor functions of CD8+ T cells in vitro. Adipocyte PD-L1 ablation obliterates, whereas forced preadipocyte PD-L1 expression confers, these inhibitory effects. Pharmacologic inhibition of adipogenesis selectively reduces PD-L1 expression in mouse adipose tissue and enhances the antitumor efficacy of anti-PD-L1 or anti-PD-1 antibodies in syngeneic mammary tumor models. Our findings provide a previously unappreciated approach to bolster anticancer immunotherapy efficacy and suggest a mechanism for the role of adipose tissue in breast cancer progression