Tissue Factor-High Ovarian Clear Cell Carcinoma Shows Immune-Cold Features and Preclinical Activity of Tisotumab...

Tissue factor (TF; encoded by F3) is frequently overexpressed in ovarian clear cell carcinoma (OCCC), but the biological features of TF-high tumors and their therapeutic implications remain poorly defined. We analyzed F3-high and F3-low OCCC using bulk RNA sequencing (n = 112) and single-nucleus RNA sequencing (n = 6; three F3-high and three F3-low cases). Bulk transcriptomic analysis showed enrichment of MYC and cell-cycle pathways in F3-high tumors, whereas immune and inflammatory pathways were enriched in F3-low tumors. Single-nucleus RNA sequencing showed that F3-high tumors contained fewer immune cells and that malignant epithelial cells displayed attenuated interferon-related programs. Transcriptomic analysis identified VTCN1, which encodes B7-H4, as upregulated in F3-high tumors and positively associated with F3 expression. Based on these findings, we evaluated TF and B7-H4 expression by immunohistochemistry in a subset of tumors (n = 56), confirming their co-expression at the protein level. In patient-derived models, higher TF expression was associated with greater sensitivity to tisotumab vedotin (TV) in vitro, and TV treatment significantly suppressed xenograft growth in vivo. These findings support TF-high OCCC as an immune-cold subgroup characterized by proliferative transcriptional programs, frequent B7-H4 co-expression, and preclinical sensitivity to TV.