Transcriptional analysis of multiple ovarian cancer cohorts reveals prognostic and immunomodulatory consequences of ERV expression
| Autor: | David J. Pinato, Haonan Lu, Anastasios Karadimitris, Ines Ullmo, Marina Natoli, Francesco Mauri, Ala Amgheib, Robert S. Brown, Sadaf Ghaem-Maghami, Teresa Marafioti, Eric O. Aboagye, Ayse U. Akarca, Jacey Ip, John Gallon |
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| Přispěvatelé: | Imperial College Healthcare NHS Trust, Genesis Research Trust |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research endocrine system diseases Endogenous retrovirus Carcinoma Ovarian Epithelial computational biology 0302 clinical medicine Immunotherapy Biomarkers Immunology and Allergy Cytotoxic T cell Intraepithelial Lymphocytes RC254-282 Oncogene Proteins Ovarian Neoplasms Interferon inducer BRCA1 Protein High-Throughput Nucleotide Sequencing Neoplasms. Tumors. Oncology. Including cancer and carcinogens Prognosis Gene Expression Regulation Neoplastic Cell killing Oncology 030220 oncology & carcinogenesis Molecular Medicine Female tumor Immunology Biology Decitabine 03 medical and health sciences interferon inducers Cell Line Tumor Cyclin E medicine Humans BRCA2 Protein Pharmacology Sequence Analysis RNA Gene Expression Profiling Endogenous Retroviruses Gene Amplification biomarkers Cancer medicine.disease Survival Analysis 030104 developmental biology Mutation Cancer cell Cancer research Ovarian cancer CD8 |
| Zdroj: | Journal for ImmunoTherapy of Cancer, Vol 9, Iss 1 (2021) Journal for Immunotherapy of Cancer |
| ISSN: | 2051-1426 |
| Popis: | BackgroundEndogenous 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.MethodsERV expression was assessed using EOC transcriptional data from The Cancer Genome Atlas (TCGA) and from an independent cohort (Hammersmith Hospital, HH), as well as from untreated or DNMTi-treated EOC cell lines. Least absolute shrinkage and selection operator (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 γδ T cells was tested in vitro, using EOC cell lines and patient-derived tumor cells.ResultsERV 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 the TCGA dataset, a higher ERV score was found in BRCA1/2 mutant tumors, compared to wild type (p=0.015), while a lower ERV score was found in CCNE1 amplified tumors, compared to wild type (p=0.019). In vitro, baseline ERV expression dictates the level of ERV induction in response to DNMTi. Manipulation of an ERV expression threshold by DNMTi resulted in improved EOC cell killing by cytotoxic immune cells.ConclusionsThese findings uncover the potential for baseline ERV expression to robustly inform EOC patient prognosis, influence tumor immune infiltration and affect antitumor immunity. |
| Databáze: | OpenAIRE |
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