Abstract
Increased number of tumor-infiltrating CD8+ lymphocytes is associated with improved survival in patients with advanced stage high grade serous ovarian cancer (HGSOC) but the underlying molecular mechanism has not been thoroughly explored. Using transcriptome profiling of microdissected HGSOC tissue with high and low CD8+ lymphocyte count and subsequent validation studies, we demonstrated that significantly increased ISG15 (Interferon-stimulated gene 15) expression in HGSOC was associated with high CD8+ lymphocyte count and with the improvement in median overall survival in both univariate and multivariate analyses. Further functional studies showed that endogenous and exogenous ISG15 suppressed ovarian cancer progression through ISGylation of ERK in HGSOC, and activation of NK cells and CD8+ T lymphocytes. These data suggest that the development of treatment strategies based on up-regulating ISG15 in ovarian cancer cells or increased circulating ISG15 in ovarian cancer patients is warranted.
Highlights
22,000 new cases of epithelial ovarian cancer will be diagnosed in the UnitedStates each year
Epithelial Interferon-stimulatedgene gene 1515 (ISG15) Protein Expression Level is Associated with Intraepithelial CD8+ T Lymphocyte Density in high grade serous ovarian cancer (HGSOC)
Since ISG15 has been shown to be secreted from monocytes and lymphocytes [16], we further evaluated whether ovarian cancer cells expressing high levels of endogenous ISG15 would secrete
Summary
22,000 new cases of epithelial ovarian cancer will be diagnosed in the United. Over 16,000 deaths per year will occur, making this cancer the most lethal gynecologic malignancy [1]. Advanced high grade serous ovarian cancer (HGSOC), which accounts for the majority of new diagnoses, is notable for initial chemotherapy sensitivity using combination platinum and taxane chemotherapy following debulking surgery [2]. The vast majority of these women will have their cancer recur within 12 to 24 months after diagnosis and will die of progressively chemotherapy-resistant tumors [3,4]. The identification of prognostic or predictive markers for ovarian cancer is crucial for the development of therapeutic targets for the improvement of patient survival.
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