BTN3A1 (Butyrophilin Subfamily 3 Member A1)

The GADEKILL γδ T and NK cells were analyzed by flow cytometry for the expression of activating and inhibitory receptors and for cytotoxicity against NB, both with and without dinutuximab-β, at a 1:1 effector-to-target ratio...Finally, NB cell lysis positively correlated with B7H6 and BTN2A1, and B7H6-blocking experiments revealed a significant decrease in target cell lysis when cells highly expressing B7H6 were used as targets. Our study demonstrated the potential antineuroblastoma activity of the GADEKILL, supporting its therapeutic use, particularly in the context of relapsed/refractory R/R HR-NB with low GD2 expression.

Active parasite invasion is required to stimulate the IFNγ response, and inhibition of the host mevalonate pathway, which limits the synthesis of the phosphoantigen isopentenyl pyrophosphate (IPP), attenuates the cytokine response, indicating Toxoplasma infection increases host phosphoantigens leading to Vγ9Vδ2 T cell activation. Our findings identify Vγ9Vδ2 T cells as key effectors that potentiate NK cells in the early human immune response to Toxoplasma, bridging innate and adaptive immunity in the absence of TLR11/12 signaling.

Besides, patients in the high-risk group exhibited lower IC50 values for vorinostat, elesclomol, OSI-906, pyrimethamine, thapsigargin, and doxorubicin, but a higher IC50 value for cisplatin, compared to those in the low-risk group, indicating differential drug sensitivities. In summary, we established a robust DRGs signature comprising BTN3A1, CEBPA, KCNAB2, TBX21, and MYC, which showed strong prognostic value and predictive potential for immune status and drug sensitivity in OS. Notably, functional experiments confirmed that BTN3A1 acted as a tumor suppressor in OS, highlighting it as a promising therapeutic target.

LC-MS showed that 6-FM-treated CHO-K1 cells accumulated substantial MPP while risedronate, an inhibitor of farnesyl diphosphate synthase, primarily increased DMAPP/IPP...Both BTN2A1 + BTN3A3-transfected CHO-K1 cells and BTN3A1 knockout K562 cells could detect 6-FM, despite their absence of BTN3A1. Our findings provide evidence that MPP functions as a natural ligand of BTN3A3 and establish a foundation for elucidating biological functions of BTN3A3 complementary to the established BTN3A1 pathway.

Our study identified molecular biomarkers for pathological and survival outcomes, which may inform optimal treatment decision-making, guide postoperative therapy, and improve survival outcomes for stage II-III patients with resectable NSCLC.

Drug sensitivity analysis revealed that BTN3A1, SIRPA, and TDO2 were correlated with the efficacy of several antineoplastic agents, including hydroxyurea and docetaxel. Validation in our clinical cohort highlighted the significant prognostic value of SIRPA, suggesting its potential as a target for immunotherapy. These findings established a framework for using immune checkpoints as prognostic biomarkers, highlighting their important role in enhancing personalized treatment strategies for OS patients.

Active parasite invasion is required to stimulate the IFNγ response, and inhibition of the host mevalonate pathway, which limits the synthesis of the phosphoantigen isopentenyl pyrophosphate (IPP), attenuates the cytokine response, indicating Toxoplasma infection increases host phosphoantigens leading to Vγ9Vδ2 T cell activation. Our findings identify Vγ9Vδ2 T cells as key effectors that potentiate NK cells in the early human immune response to Toxoplasma , bridging innate and adaptive immunity in the absence of TLR11/12 signaling.

This review provides a detailed overview of the historical progress and recent discoveries regarding how Vγ9Vδ2 T cells recognize and target tumor cells. We also discuss the potential of γδ T cells immunotherapy and their role as antitumor agents.

Our study uncovers a "plier-like gripping" mechanism, where BTN multimers bridge the TCR surface to drive activation. These findings establish a structural foundation for γδ T cell-targeted immunotherapies distinct from αβ T cell strategies reliant on major-histocompatibility-complex-mediated antigen presentation.

Cryo-EM reveals that BTN2A1-BTN3A1-BTN3A2 binds two γδ TCR ectodomains, with one being sandwiched between the IgV domains of BTN2A1 and BTN3A2, while the other interacts with the free BTN2A1 IgV in the complex, as evidenced by functional data. Together, our findings uncover the mechanism of ligand-induced inside-out stabilization of BTN receptor complexes for dimeric activation of γδ TCR.

The institution of Dr. Levy has received research support from National Institutes Health.

Moreover, Vγ9Vδ2 T cells can restore the tumoricidal function of αβ T cell through competitively binding to BTN3A1, a TCR-Vγ9Vδ2 ligand on CC cells upregulated by IFN-γ derived from activated αβ T cell. These findings uncover a critical synergistic effect of autologous Vγ9Vδ2 T cells and αβ T cells in immunotherapy of CC and reveal the underlying mechanisms.