Immune mediator expression signatures are associated with improved outcome in ovarian carcinoma

Abstract

Immune and inflammatory cascades may play multiple roles in ovarian cancer. We aimed to identify relationships between expression of immune and inflammatory mediators and patient outcomes. We interrogated differential gene expression of 44 markers and marker combinations (n = 1,978) in 1,656 ovarian carcinoma patient tumors, alongside matched 5-year overall survival (OS) data in silico. Using machine learning methods, we investigated whether genomic expression of these 44 mediators can discriminate between malignant and non-malignant tissues in 839 ovarian cancer and 115 nonmalignant ovary samples. We furthermore assessed inflammation markers in 289 ovarian cancer patients' sera in the Swedish Apolipoprotein MOrtality-related RISk (AMORIS) cohort. Expression of the 44 mediators could discriminate between malignant and non-malignant tissues with at least 96% accuracy. Higher expression of classical Th1, Th2, Th17, anti-parasitic/infection and M1 macrophage mediator signatures were associated with better OS. Contrastingly, inflammatory and angiogenic mediators, CXCL-12, C-reactive protein (CRP) and platelet-derived growth factor subunit A (PDGFA) were negatively associated with OS. Of the serum inflammatory markers in the AMORIS cohort, women with ovarian cancer who had elevated levels of haptoglobin (≥1.4 g/L) had a higher risk of dying from ovarian cancer compared to those with haptoglobin levels <1.4 g/L (HR = 2.09, 95% CI:1.38-3.16). Our findings indicate that elevated "classical" immune mediators, associated with response to pathogen antigen challenge, may confer immunological advantage in ovarian cancer, while inflammatory markers appear to have negative prognostic value. These highlight associations between immune protection, inflammation and clinical outcomes, and offer opportunities for patient stratification based on secretome markers.

Clinical usefulness of high levels of C-reactive protein for diagnosing epithelial ovarian cancer

“…High levels of CRP have been associated with the risk for several chronic conditions, including cardiovascular disease, atherosclerosis, and cancer 15 , 17 – 19 . Investigators have reported that plasma CRP concentrations are increased in response to inflammation, which may promote tumor growth and metastasis in breast cancer and ovarian cancer 15 , 20 , 21 . However, additional clinical evidence is needed to prove a diagnostic role for CRP in EOC.…”

Assessment of peritoneal microbial features and tumor marker levels as potential diagnostic tools for ovarian cancer

“…The functionality of the microbial features varied but was centralized around inflammatory mediators. It is widely known that the pathogenesis of OC induces peritoneal inflammation and that this is one possible mechanism for disease metastasis [55][56][57][58]. Of particular interest, we found 3 different microbial features that may be directly related to disease pathogenesis; estrogen responsiveness (Rikenellaceae (order) of the Bacteroidetes (Phylum)), vascular permeability (Alphaproteobacteria (Class) of the Proteobacteria (Phylum)) and antiinflammatory properties (Akkermansia; muciniphila of the Verrucomicrobia (Phylum)).…”

Zoledronic Acid Abrogates Restraint Stress-Induced Macrophage Infiltration, PDGF-AA Expression, and Ovarian Cancer Growth

“…In order to understand the potential role of the different subtypes of macrophages under adrenergic stimuli, we analyzed changes in subsets of cytokine signatures in our U937 monoculture and SKOV3ip1/U937 co-culture systems. Here, we utilized existing data from ovarian carcinoma immune profiling studies [ 16 , 17 , 18 ] to determine if there are changes in cytokine signatures suggestive of M1, M2, and TAMs phenotypes ( Figure 3 a). The results show that NE-treated SKOV3ip1/U937 co-cultures express significantly more factors from a TAMs signature compared to NE-treated U937 macrophages alone.…”

“…More importantly, high levels of PDGF-AA expression were also correlated with poor survival in cervical squamous cell carcinoma, glioblastoma multiforme, and kidney renal clear cell carcinoma [ 35 ]. Recent studies have explored the inflammatory expression signatures in ovarian cancers, in which elevated expression of intratumoral PDGFA was found to increase the risk of death and correlate with adverse outcomes [ 18 ]. In vitro PDGFRα blockade with IMC-3G3, a specific monoclonal antibody, in combination with docetaxel sensitized HeyA8-MDR ovarian cancer cells and induced apoptosis.…”