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Transcriptional profiling of ovarian tumours and cell lines

ABSTRACT: Purpose: Endogenous retroviruses (ERVs) play a role in a variety of biological processes, including embryogenesis and cancer. DNA methyltransferase inhibitors (DNMTi)-induced ERV expression triggers interferon responses in ovarian cancer cells via the viral sensing machinery. Baseline expression of ERVs also occurs in cancer cells, though this process is poorly understood and previously unexplored in epithelial ovarian cancer (EOC). Here, the prognostic and immunomodulatory consequences of baseline ERV expression was assessed in EOC. Experimental Design: ERV expression was assessed using EOC transcriptional data from TCGA and from an independent cohort (HH), as well as from untreated or DNMTi-treated EOC cell lines. LASSO logistic regression defined an ERV expression score to predict patient prognosis. Immunohistochemistry (IHC) was conducted on the HH cohort. Combination of DNMTi treatment with ÃŽÂ³ÃŽÂ´ T cells was tested in vitro, using EOC cell lines and patient-derived tumor cells. Results: ERV expression was found to define clinically relevant subsets of EOC patients. An ERV prognostic score was successfully generated in TCGA and validated in the independent cohort. In EOC patients from this cohort, a high ERV score was associated with better survival (log-rank p=0.0009) and correlated with infiltration of CD8+PD1+ T cells (r=0.46, p=0.0001). In vitro, baseline ERV expression dictates the level of ERV induction in response to DNMTi. Manipulation of ERV expression by DNMTi resulted in improved EOC cell killing by cytotoxic immune cells. Conclusions: These findings uncover the potential for baseline ERV expression to robustly inform EOC patient prognosis, influence tumor immune infiltration and affect anti-tumor immunity.

PROVIDER: EGAS00001004814 | EGA |

REPOSITORIES: EGA

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Project description:Background: In previous studies we showed that IL-27 shares several effects with IFN-γ in human cancer cells. To identify novel extracellular mediators, potentially involved in epithelial ovarian cancer (EOC) biology, we analyzed the effect of IL-27 or IFN-γ on the secretome of EOC cells in culture. Methods: The secretome of cytokine-treated or untreated SKOV3 cells was analyzed by nano-UHPLC-MS/MS and eluting peptides by an Orbitrap Fusion Tribrid mass spectrometer. Extracellular GBP1 was studied by ELISA, immunoprecipitation, GTP-agarose pull-down, and Western blotting. GBP and STAT proteins were analysed on cell lysates by Western blot. GBP1 was transfected using lipofectamine reagent and cell viability measured by MTT assay. Results: IL-27 and IFN-γ modulate the extracellular release of a limited fraction of proteins that were also induced in the whole cell. Among these proteins we focused our attention on GBP1, a guanylate-binding protein and GTPase, which is a mediator of several biological activities of IFNs. Interestingly GBP1, 2, and 5 were induced by cytokine treatment in EOC cells, but only GBP1 was secreted. ELISA and immuno-blotting analyses showed that cytokine-stimulated EOC cells release full-length GBP1 molecule in vitro, through non-classical pathways, not involving microvesicles. Moreover, soluble, full-length GBP1 accumulates in the ascites of most EOC patients, suggesting a potential role of extracellular GBP1 in the tumor environment. EOC cells enriched from ascites showed constitutive tyrosine-phosphorylated STAT1 and STAT3 proteins and GBP1 expression, supporting a role of STAT-activating cytokines in GBP1 induction in vivo. Data from the TCGA dataset of EOC indicate that high GBP1 gene expression correlates with a better overall survival. Accordingly GBP1 transfection reduced SKOV3 cell proliferation, suggesting a potential anti-tumor activity of GBP1. Conclusions: Our data show for the first time that soluble GBP1 is released by cytokine-stimulated EOC cells in vitro and accumulates in EOC patients’ ascites. GBP1 expression may have anti-tumor effects, in EOC, as suggested by TCGA dataset analysis and in vitro transfection experiments. Further studies to identify the biological role of soluble GBP1 in the tumor environment of EOC are warranted.

Project description:Purpose: We aimed to investigate the distinct transcriptional landscape in the poor responders to concurrent chemoradiotherapy (CCRT) and to gain mechanistic insights on treatment resistance in cervical cancer. Methods: RNA sequencing was performed using archived pre-treatment tissue biopsies of patients with locally advanced cervical cancer treated with concurrent platinum-based CCRT. Transcriptome data of patients with no durable benefit (NDB; progression-free period < 3 years) and durable clinical benefit (DCB; progression-free period > 5 years) after were compared. NDB score was estimated for each patient using the differentially expressed genes between NDB and DCB patients. Three independent cohorts, including The Cancer Genome Atlas cervical cancer (TCGA-CESC) cohort, were utilized for validation of NDB score. Potential response to PD-1 blockade was estimated with Tumor Immune Dysfunction and Exclusion (TIDE) score and T-cell-inflamed gene expression profile (GEP). Results: Patients with NDB exhibited a distinct transcriptional profile compared to those with DCB such as higher signatures of extracellular matrix organization and epithelial-to-mesenchymal transition. The fraction of cancer-associated fibroblasts (CAFs) within the tumor was significantly higher in NDB than DCB patients. Higher NDB score was significantly associated with poor survival in the TCGA-CESC cohort (n = 274; P = 0.015), but only in patients that received curative aim radiotherapy (P = 0.002) and not in patients who received other treatments (P = 0.57). The transcriptomic characteristics of patients with NDB were recapitulated in patients with high NDB score in TCGA-CESC. Patients with high NDB score displayed significantly higher TIDE prediction score and lower T-cell-inflamed GEP score compared to patients with low NDB scores. Conclusion: Cervical cancer patients with poor treatment outcome following CCRT exhibited a distinct gene signature that was able to predict treatment outcomes. For poor responders, immune checkpoint inhibitors may be less effective and CAF-targeting treatments may be a promising approach.

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Transcriptional profiling of ovarian tumours and cell lines

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