ABSTRACT 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.
Mori et al. (Sun,) studied this question.