Abstract 6163: PARP inhibition induces the expression of interferon-response genes in both BRCAm and BRCAwt high grade serous ovarian cancer cells

Abstract Background: Therapeutic synergy of PARP inhibition (PARPi) and CTLA4 immune checkpoint inhibition (ICI) in BRCA1 mutated (BRCAm) ovarian cancer (OC) models was dependent on increased interferon gamma (IFNg) production in the tumor microenvironment (TME). Expression of interferon-response genes in tumor samples is also linked with CTLA4 ICI efficacy in melanoma. In an assessment of interferon-response gene expression in tumor samples from women with BRCAm ovarian cancer enrolled in a phase I/II clinical trial of PARPi and CTLA4 ICI, IFIT1B was significantly associated with both treatment benefit (AUC=0.842), and progression-free survival (PFS) (n=30, p=0.029). In this cohort, IFIT1B expression was also strongly correlated with other IFIT gene family members, and positively correlated with CXCL10 expression among subjects with clinical benefit from treatment. In an analysis of TCGA data, IFIT1B expression was also significantly associated with PFS among BRCAm patients (n=16, p=0.0306), but not in the larger ovarian cancer cohort (n=299, p=0.1953). IFIT gene family expression is induced by type I and type II interferons, as well as cytosolic nucleic acid sensing. CXCL10 expression is associated with anti-tumor immunity and is prognostic in ovarian cancer. Objective: To examine the association between these candidate biomarkers and treatment outcomes, we exposed murine OC cells to PARPi, IFNg, or the combination in vitro, and compared gene expression by qPCR and production of CXCL10 and IFN beta by ELISA. Results: Treatment with PARPi significantly increased expression of IFIT family members (Ifit1, Ifit2, Ifit3) compared with untreated cells, and additionally increased expression in combination with IFNg compared with IFNg exposure alone. PARPi-induced IFIT gene expression was independent of BRCA status and was observed in both PARPi-sensitive and -resistant BRCA1m models. PARPi also significantly increased expression of CXCL10 by qPCR, and PARPi in combination with IFNg increased levels of secreted CXCL10 by BRCA1m cells compared with IFNg alone. Although expression of IFNb was similar across all treatment conditions, high IFN beta secretion was observed in BRCA1m cells treated with PAPRi in combination with IFNg. Conclusions: These results indicate that PARPi can modulate tumor cell-intrinsic responses to IFNg independent of BRCAm status, including changes in secreted chemokines and cytokines associated with T cell recruitment and immune activation in the tumor microenvironment. With evidence that both IFN signaling and CXCL10 in the TME can impact treatment efficacy and disease outcomes, these data may inform the design of novel combinatorial regimens for ovarian cancer. Citation Format: Daniel Falcon, Alyson Yeckes, Ania Klas, Andrea Corbet, Chelsea Goff, Sandra Orsulic, Rita Serda, Phyllis Gimotty, Sarah Adams. PARP inhibition induces the expression of interferon-response genes in both BRCAm and BRCAwt high grade serous ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6163.