Tumor Cells Enriched for Interferon and Inflammatory Programs Pre-Exist in High Grade Serous Ovarian Cancer and are Proportionately Significantly Increased Post Chemotherapy

Winterhoff, B. J.; Girnius, N. A.; Liu, M.; Kang, J.; Shetty, M.; Martinez-Gakidis, M. A.; Xu, W.; Thomas, M.; Lahmadi, L.; Henstridge, A. Z.; Baldominos, P.; Talukdaer, S.; Chang, Z.; Mattson, J.; Gruner, M.; Mullany, S. A.; Argenta, P.; Konecny, G. E.; Slamon, D. J.; Drapkin, R.; Nelson, A. C.; Starr, T. K.; Brugge, J. S.

doi:10.1101/2025.06.24.661404

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bioRxiv · 10.1101/2025.06.24.661404

Tumor Cells Enriched for Interferon and Inflammatory Programs Pre-Exist in High Grade Serous Ovarian Cancer and are Proportionately Significantly Increased Post Chemotherapy

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Abstract

Drug-tolerant, high-grade serous ovarian cancer (HGSOC) cells that persist after first-line chemotherapy and subsequently relapse often retain sensitivity to secondary treatment, suggesting a therapeutic window before stable chemoresistance emerges. We performed single-cell RNA sequencing (scRNA-seq) on seven matched pairs of tumors, collected pre- and post-chemotherapy, to define vulnerabilities in these reversibly-resistant cells. Treatment induced a marked enrichment of tumor and stromal cell populations expressing correlated interferon (IFN) and inflammatory (IFM) gene signatures, with a concurrent depletion of proliferation-related and MYC-associated states in the tumor cells. Cross-cohort single cell sequencing analysis of >130 treatment-naive tumors revealed heterogeneity in the abundance of IFN/IFM-expressing cells. Multiplex immunofluorescence imaging of IFN-stimulated gene (ISG) products confirmed the presence of spatially clustered ISG-positive tumor cells in all cases, as well as in serous tubal intraepithelial carcinomas (STIC lesions), the presumptive HGSOC precursors. ISG expression correlated strongly with ORF1P, a protein encoded by the endogenous retrotransposon LINE1. These data suggest that early oncogenic events drive LINE1 derepression and innate immune activation, establishing an IFN-rich transcriptional state that persists in tumor subpopulations and is strongly enhanced by chemotherapy.

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Winterhoff, B. J., Girnius, N. A., Liu, M., Kang, J., Shetty, M., Martinez-Gakidis, M. A., Xu, W., Thomas, M., Lahmadi, L., Henstridge, A. Z., Baldominos, P., Talukdaer, S., Chang, Z., Mattson, J., Gruner, M., Mullany, S. A., Argenta, P., Konecny, G. E., Slamon, D. J., Drapkin, R., Nelson, A. C., Starr, T. K., Brugge, J. S.. 2025-06-25. Tumor Cells Enriched for Interferon and Inflammatory Programs Pre-Exist in High Grade Serous Ovarian Cancer and are Proportionately Significantly Increased Post Chemotherapy. https://doi.org/10.1101/2025.06.24.661404

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