Ovarian cancer (OC) is the most lethal gynecological malignancy, with platinum‐based chemotherapy remaining the mainstay for adjuvant treatment after surgery. The lack of indication for immunotherapy may at least in part result from the lack of suitable biomarkers allowing stratification of potentially responding patients. In this monocentric study of 141 cases with OC, we used real‐time quantitative PCR to assess the expression of retinoic acid‐inducible gene‐I (RIG‐I) in primary tumor and healthy ovarian control tissues. RIG‐I expression was correlated to various clinicopathological characteristics as well as to a set of molecular and immunological markers. The prognostic significance of RIG‐I expression was queried in univariate and multivariate analyses and validated in an independent cohort. RIG‐I was overexpressed in the cancerous ovary and correlated with a higher tumor grade. The more aggressive Type‐II cancers and cancers with inactivating p53 mutations exhibited higher RIG‐I expression. RIG‐I levels were also elevated in cancers that recurred after remission or were platinum‐refractory. Survival analyses disclosed RIG‐I as an independent marker of poor outcome in OC. Continuative analyses revealed the molecular and immunological correlates of RIG‐I expression in the tumor microenvironment, including interferon production and a distinct immune‐regulatory signature involving checkpoint molecules (PD‐L1/PD‐1), the RNA‐editing enzyme ADAR1 and the regulatory T cell‐specific transcription factor FoxP3. We conclude that high RIG‐I expression associates with poor outcome in OC, which is explainable by local immunosuppression in the tumor bed. RIG‐I expression may inform checkpoint blockade and/or RIG‐I agonistic targeting in a subset of high‐risk OC patients.

Epithelial ovarian cancer (OC) is the deadliest gynecological malignancy worldwide. Blocking angiogenesis with bevacizumab, an antibody targeting vascular endothelial growth factor (VEGF), shows efficacy in different lines of OC therapy. This study investigates the clinical impact of tumoral expression of angiogenesis-related genes and their association with bevacizumab response in OC in retrospective analysis of three independent cohorts. mRNA expression of seven angiogenic genes (VEGF, VEGFR2, PDGFA, PDGFB, PDGFRA, PDGFRB, KIT) was quantified in an inception OC cohort (n = 195) and a transcriptional tumor angiogenesis score from 0 to 3 was established and linked to progression-free survival (PFS) and overall survival (OS). This score was corroborated in an independent publicly available cohort from The Cancer Genome Atlas (TCGA, n = 582) and prediction of therapeutic efficacy of bevacizumab by the angiogenesis score was analyzed in the Gene Expression Omnibus (GEO) dataset GSE140082 (n = 380) from the ICON7-trial. The tumor angiogenesis score prognosticated PFS and OS in patients with OC from the inception cohort (p < 0.001, respectively). Tumoral PDGFA expression (PFS: HR 2.46, p = 0.005; OS: HR 2.26, p = 0.011) and a high tumoral transcriptional angiogenesis score (PFS: HR 1.41, p = 0.018) were identified as independent predictors of clinical outcome. The transcriptional angiogenesis score exhibited a significant though smaller effect size on PFS in the TCGA cohort. However, in the ICON7-trial, the angiogenesis score was not associated with benefit of bevacizumab treatment. Our study indicates that tumoral expression of angiogenic genes is unfavorable in OC. The established score could be used to identify patients who respond to targeted angiogenic therapies, a concept that warrants prospective controlled clinical trials.

Ovarian cancer (OC) is a gynaecological malignancy with poor clinical outcome and limited treatment options. The receptor activator of nuclear factor-κB (RANK) pathway, activated by RANK ligand (RANKL), critically controls bone metabolism, tumourigenesis and tumour immune responses. Denosumab, a monocloncal RANKL antibody, exerts tumour-suppressive effects in mice and humans. Here, we investigated the relevance of RANK signalling in OC. RANK, RANKL and OPG expression in 192 epithelial OC tissues was compared to expression in 35 non-malignant control tissues and related to clinico-pathological characteristics. Findings were validated in a cohort of 563 OC patients from The Cancer Genome Atlas (TCGA). The expression of RANK, RANKL and OPG was studied in four OC cell lines and the impact of RANK ligation or blockade on OC cell proliferation was determined. RANK, RANKL and OPG were expressed in epithelial and stromal cells in OC. RANKL expression was elevated in OC tissue, particularly in BRCA1/2 mutated tumours. High RANKL expression independently predicted reduced progression-free (PFS, p = 0.017) and overall survival (OS, p = 0.007), which could be validated in the TCGA cohort (PFS, p = 0.022; OS, p = 0.046, respectively). Expression of RANK and OPG in OC cells was induced by inflammatory cytokines IL-1β and TNFα. Neither recombinant RANK ligation nor denosumab treatment affected OC cell proliferation. Our study independently links RANKL expression with poor clinical outcome in two unrelated OC cohorts. These findings implicate RANK signalling in the immunopathogenesis of OC and warrant clinical trials with denosumab in OC.

Ovarian cancer (OC) is the foremost lethal gynaecologic malignancy and among the top five deadliest cancers in women. Current treatment comprises a combination therapy of surgery, platinum-based chemotherapy and anti-vascular endothelial growth factor (VEGF) antibodies. However, patients typically experience a disease relapse within two years. Recurrent OC is incurable and resistance to platins and anti-VEGF treatment is a major determinant of prognosis. Understanding the molecular mechanisms that contribute to tumour metastasis and chemoresistance are essential to improve patient outcome and especially survival. In a current OC model, tumour metastasis and chemoresistance critically depend on the biology of cancer stem cells (CSCs). Recent studies also suggest that intratumour heterogeneity is the main cause of treatment failure due to chemoresistance. Furthermore, the proinflammatory tumour microenvironment seems to contribute to metastasis and chemoresistance. Despite an improved understanding of the complex interplay between classical mechanisms of drug inactivation or efflux, clonal selection and the tumour microenvironment, mechanisms of resistance in human OC are poorly understood. This review summarises current concepts in the treatment of OC, mechanisms of resistance to chemotherapy and angiogenic inhibitors and approaches to overcome drug resistance.

Inflammation plays a crucial role in the pathogenesis of cancer with tumor necrosis factor‐α (TNF‐α) as a key mediator. Recently, spermatogenesis‐associated protein 2 (SPATA2) was identified as a TNF receptor modulator which is required for TNF‐induced inflammation and apoptosis. The available data on TNF‐α in ovarian cancer (OC) are inconsistent, and SPATA2 is completely uncharacterized in tumorigenesis. We analyzed expression of SPATA2 and TNFA by quantitative real‐time polymerase chain reaction in tissues of 171 patients with low‐grade serous (LGSOC), high‐grade serous (HGSOC), endometrioid and clear cell OC compared with 28 non‐malignant control tissues. We stimulated OC cells (OVCAR3) with pro‐inflammatory (TNF‐α, interleukin [IL]‐1β) and mitogenic stimuli (IL‐6, lysophosphatidic acid) to establish a direct effect between inflammatory signaling and SPATA2. Pro‐inflammatory, but not mitogenic stimuli, potently induced SPATA2 expression in OC cells. Expression of TNFA and SPATA2 was higher in OC compared with control tissues (P = 0.010 and P = 0.001, respectively) and correlated with each other (P = 0.034, r_s = 0.198). When compared with grade 1 cancers, SPATA2 was expressed higher in grade 2 and 3 tumors (P = 0.011) as well as in HGSOC compared with LGSOC (P = 0.024). Multivariate survival analyses revealed that OC with high SPATA2 expression were associated with reduced progression‐free survival (P = 0.048) and overall survival (P < 0.001). In conclusion, SPATA2 expression is regulated by TNF‐α and IL‐1β and is found to independently affect clinical outcome in OC patients. These data implicate a role of SPATA2 in tumorigenesis which warrants further investigation in gynecological malignancies.

Aim/Background: Check point molecules such as programmed cell death protein (PD-1) and its ligand PD-L1 have emerged as potential targets in cancer immunotherapy as antibodies against these molecules can potentially restore T-cell tumourigenicity and suppress tumour growth. The purpose of this study was to investigate an association between PD-1 and PD-L1 expression in ovarian cancer (OC).