High‐grade serous ovarian carcinoma (HGSC) accounts for 70% of all epithelial ovarian cancers but clinical management is challenged by a lack of accurate prognostic and predictive biomarkers of chemotherapy response. This study evaluated the role of Signal Transducer and Activator of Transcription 1 (STAT1) as an independent prognostic and predictive biomarker and its correlation with intratumoural CD8+ T cells in a second independent biomarker validation study. Tumour STAT1 expression and intratumoural CD8+ T cell infiltration were assessed by immunohistochemistry as a multicentre validation study conducted on 734 chemotherapy‐naïve HGSCs. NanoString‐based profiling was performed to correlate expression of STAT1 target genes CXCL9, CXCL10 and CXCL11 with CD8A transcript expression in 143 primary tumours. Multiplexed cytokine analysis of pre‐treatment plasma from resistant and sensitive patients was performed to assess systemic levels of STAT1‐induced cytokines. STAT1 was validated as a prognostic and predictive biomarker in both univariate and multivariate models and its expression correlated significantly with intra‐epithelial CD8+ T cell infiltration in HGSC. STAT1 levels increased the prognostic and predictive value of intratumoural CD8+ T cells, confirming their synergistic role as biomarkers in HGSC. In addition, expression of STAT1 target genes (CXCL9, CXCL10 and CXCL11) correlated significantly with levels of, and CD8A transcripts from intratumoural CD8+ T cells within the resistant and sensitive tumours. Our findings provide compelling evidence that high levels of STAT1, STAT1‐induced chemokines and CD8+ T cells correlate with improved chemotherapy response in HGSC. These results identify STAT1 and its target genes as novel biomarkers of chemosensitivity in HGSC. These findings provide new translational opportunities for patient stratification for immunotherapies based on emerging biomarkers of inflammation in HGSC. An improved understanding of the role of interferon‐inducible genes will be foundational for developing immunomodulatory therapies in ovarian cancer.

High-grade serous ovarian cancer remains one of the most lethal malignancies in women. Despite recent advances in surgical and pharmaceutical therapies, survival rates remain poor. A major impediment in management of this disease, that continues to contribute to poor overall survival rates, is resistance to standard carboplatin-paclitaxel combination chemotherapies. In addition to tumor cell intrinsic mechanisms leading to drug resistance, there is increasing awareness of the crucial role of the tumor microenvironment in mediating natural immune defense mechanisms and selective pressures that appear to facilitate chemotherapy sensitivity. We provide an overview of some of the promising new genetic and immunological biomarkers in ovarian cancer and discuss their biology and their likely clinical utility in future ovarian cancer management.

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Chemotherapy resistance is a major hurdle in high-grade serous epithelial ovarian cancer (HGSC) management. We previously reported differential expression of interferon inducible genes in pre-treatment tumours from chemoresistant and sensitive HGSC tumors. STAT1 expression was evaluated as a prognostic and predictive biomarker via immunohistochemistry in Phase I (n = 183) and Phase II (n = 550) biomarker validation studies conducted on HGSC tumours accrued from the Terry Fox Research Institute- Canadian Ovarian Experimental Unified Resource (TFRI-COEUR). Tumor STAT1 expression levels significantly correlated with the density of tumor infiltrating CD8+ T lymphocytes in both Phase I and Phase II cohorts. STAT1 expression significantly associated with progression free survival and response to chemotherapy in both Phase I and Phase II validation studies. Significant positive correlation between STAT1 expression levels and intratumoral CD8+ T cell density was observed. Intratumoral CD8+ T cell infiltration did not associate with progression free survival or response to chemotherapy in both cohorts. Interestingly, the prognostic relevance of CD8+ T cell was enhanced in combination with STAT1 in both cohorts. These findings provide evidence that STAT1 as an independent biomarker and a combination of CD8+ T cell infiltration with STAT1 could be novel immune-based prognostic and predictive biomarkers in HGSC. Findings from the current study will aid in patient stratification for novel immunomodulatory therapies for the management of chemotherapy resistance in HGSC. Citation Format: Katrina K. Au, Liliane Meunier, Cécile Le Page, Charles H. Graham, Andrew WB Craig, Timothy Childs, Julie-Ann Francis, Jeremy Squire, Anne-Marie Mes-Masson, Madhuri Koti. Association of interferon inducible genes with tumor immune microenvironment and chemotherapy resistance in high-grade serous epithelial ovarian cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 441.

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