Abstract
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.
Highlights
We found that Retinoic acid-inducible gene-I (RIG-I) levels were significantly higher in the cancerous ovary, suggesting aberrant RIG-I gene expression during the process of malignant transformation (p = 0.001, Fig. 1a)
Tumor cell-specific PD-L1 expression was only detected in the RIG-I high-expressing setting, while PD-L1 expression in RIG-I low-expressing tumors was exclusive to immune/hematopoietic cells. These data suggest that the activation of RIG-I in ovarian tumors is paralleled by a distinct regulatory program involving various mechanisms and pathways, an effect that may limit the innate immune response to a level that no longer constraints, but rather supports, tumor growth. In this single-center, retrospective, explorative biomarker study of 141 cases with epithelial Ovarian cancer (OC), we uncovered the prognostic significance of the innate immune receptor helicase RIG-I, whose canonical function in physiology is to elicit an antiviral response after pattern-based recognition of viral RNA.[7,8]
Upregulated in the malignant ovary, RIG-I associated with certain clinicopathological characteristics such as tumor grade, while showing virtual independence from others including histological subtype and postoperative tumor burden
Summary
Ovarian cancer (OC) is the most lethal gynecological tumor and mainly two factors account for this detrimental clinical the inherently aggressive nature of this malignancy driven at least in part by persistence of chemo-resistant cancer stem cells and subclonal diversification.[3,4] OC presents as a heterogeneous disease, treatment options are rather uniform and generally involve surgical debulking followed by adjuvant therapy with platinum-based compounds, frequently in combination with taxanes.[1,2] Considering the various histological subtypes[5] and the dualistic pathogenesis that underlies OC,[6] this is a quite unsatisfactory condition and clearly in conflict with the proclaimed goal of delivering precision medicine.novel prognostic and/or predictive biomarkers are desirable to refine patient stratification and tailor treatment for improved outcomes.Retinoic acid-inducible gene-I (RIG-I) is an innate immune receptor helicase facilitating pattern recognition of 50-triphosphate RNA produced by viral polymerases upon infection.[7,8] RIG-I is broadly expressed in various tissues and cell types (including hematopoietic, epithelial and neuronal cells) and becomes greatly induced after viral encounter.[9]. Ovarian cancer (OC) is the most lethal gynecological tumor and mainly two factors account for this detrimental clinical the inherently aggressive nature of this malignancy driven at least in part by persistence of chemo-resistant cancer stem cells and subclonal diversification.[3,4]. OC presents as a heterogeneous disease, treatment options are rather uniform and generally involve surgical debulking followed by adjuvant therapy with platinum-based compounds, frequently in combination with taxanes.[1,2]. Novel prognostic and/or predictive biomarkers are desirable to refine patient stratification and tailor treatment for improved outcomes. Retinoic acid-inducible gene-I (RIG-I) is an innate immune receptor helicase facilitating pattern recognition of 50-triphosphate RNA produced by viral polymerases upon infection.[7,8]. RIG-I is broadly expressed in various tissues and cell types (including hematopoietic, epithelial and neuronal cells) and becomes greatly induced after viral encounter.[9]. RIG-I recognizes different types of RNA viruses[10] and subsequently initiates
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
