Abstract
Objective: The main objective of the present study was to explore contact-independent immune suppressive mechanisms by humoral factors in malignant ascites from ovarian carcinoma that target effector T cells. Methods: Flow cytometry was the main method used to detect T cell function as assessed by CFSE-proliferation rate, in the presence of different concentrations of ascites fluid. Cell-free ascites was sometimes pretreated using a biochemical approach. Different antibody inhibitors were used to reverse the ascites-induced inhibition of T cell proliferation. Results: By culturing T cells in cell-free ascites we demonstrated malignant ascites fluid to be highly immunosuppressive both against autologous and allogeneic T cells (n=6, p<0,001). The inhibitory factor(s) in ascites did not appear to be secreted from the ovarian carcinoma (OC) cells, as transfer of culture media from tumor cells isolated from OC patients or the ovarian cancer cell-line SKOV-3 did not suppress effector T cell functions in vitro. A more detailed characterization demonstrated that the inhibition could not be reversed by targeting potential suppressive mechanisms like IL-6, IL-8, IL-10, CTLA-4, PD-1, B7-DC, B7-H1 or PI3K (n=5). Furthermore, we found the inhibitory factor(s) to be sensitive to proteases and denatured by heat and acetone (n=3). Conclusion: In conclusion, our data indicate the presence of a yet unknown inhibitory protein factor(s) in malignant cell-free ascites, not secreted by tumor cells, but possibly by immune cells such as regulatory T cells (Tregs).
Highlights
Ovarian carcinoma (OC) is the sixth most common malignant neoplasm among females and the leading cause of death from gynecological malignancies [1,2]
Progressing OC spreads from the epithelium of the ovaries into the peritoneal cavity, and leads to production of malignant ascites [6]
As the malignant cells extend into the peritoneal cavity, they remain confined in direct contact with the intraperitoneal fluid, both as free-floating tumor cells and embedded in the peritoneal lining [7]
Summary
Ovarian carcinoma (OC) is the sixth most common malignant neoplasm among females and the leading cause of death from gynecological malignancies [1,2]. Regardless of cytoreductive surgery and chemotherapeutic regimens, the overall survival rate remains below 40% [3]. This is mainly due to inherent or acquired drug resistance and the fact that most tumors have developed to an advanced stage at the time of diagnosis [4]. Progressing OC spreads from the epithelium of the ovaries into the peritoneal cavity, and leads to production of malignant ascites [6]. As the malignant cells extend into the peritoneal cavity, they remain confined in direct contact with the intraperitoneal fluid, both as free-floating tumor cells and embedded in the peritoneal lining [7]
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