重定向 T 细胞细胞毒性揭示 BRD9-PTGES 轴是卵巢癌中的免疫增敏脆弱靶点

Ovarian cancer shows limited responsiveness to immune checkpoint blockade, suggesting that malignant cells harbor intrinsic programs capable of suppressing T cell-mediated antitumor immunity. To uncover these programs under fixed recognition signal conditions, the research team established and optimized a B7H3×CD3-based, MHC-independent redirected cytotoxicity platform, which generated a reproducible partial-killing window. By screening 1796 bioactive compounds in paired SKOV3 monocultures and SKOV3/PBMC co-cultures, the researchers distinguished immune-sensitizing perturbations from direct cytotoxic agents and identified I-BRD9, a selective BRD9 bromodomain inhibitor, as a top candidate.

I-BRD9 enhanced T cell-mediated killing in ovarian cancer models, B7-H3-positive benchmark cell lines, and patient-derived ovarian tumor suspensions, without affecting tumor cell or PBMC viability. Cross-cell line RNA-seq analysis revealed that BRD9 inhibition reshapes a coordinated immune resistance program involving PGE2 biosynthesis, inhibitory ligands, T cell-attracting chemokines, antigen presentation-related transcripts, and extracellular matrix features.

Within this program, siRNA-mediated PTGES knockdown functionally recapitulated key effects of I-BRD9 by restoring chemokine/PGE2-axis transcripts, promoting CD8 + T-cell proliferation and IFN-γ production, and enhancing T-cell effector-associated gene expression.

These findings establish the BRD9-PTGES/PGE2 axis as an actionable tumor-intrinsic pathway that limits ovarian cancer sensitivity to T cell-mediated cytotoxicity.