Natural Killer Cells Response to IL-2 Stimulation Is Distinct between Ascites with the Presence or Absence of Malignant Cells in Ovarian Cancer Patients

Abstract

Peritoneal ascites are a distinguishable feature of patients with advanced epithelial ovarian cancer (EOC). The presence of different lymphocyte subsets has been reported in EOC-associated ascites, which also can or not contain malignant cells. The goal of this study was to analyze the functional characteristics of natural killer (NK) cells from EOC-associated ascites in terms of their expression of activating receptors and ascites’ contents of lymphocyte subtypes, cytokine profile and presence of EOC cells. NK cell function was evaluated by the expression of the degranulation marker CD107a in resting and interleukin (IL)-2 stimulated NK cells from ascites and blood. Degranulation of NK cells from EOC cell-free ascites was significantly (p < 0.05) higher than all the other groups, either in their resting state or after IL-2 stimulation, suggesting a previous local stimulation. In contrast, treatment with IL-2 had no effect on NK cells from ascites with EOC cells. The amount of regulatory T cells was significantly higher in ascites with EOC cells compared to EOC cell-free ascites. Ascites with EOC cells also had higher levels of tumor necrosis factor (TNF)-α, suggesting inflammation related to the malignancy. In conclusion, the functional performance of NK cells was distinct between EOC cell-free ascites and ascites with EOC cells. The impairment of NK cell response to IL-2 in ascites with EOC cells was consistent with an immunosuppressive tumor microenvironment.

Interleukin 6 Present in Inflammatory Ascites from Advanced Epithelial Ovarian Cancer Patients Promotes Tumor Necrosis Factor Receptor 2-Expressing Regulatory T Cells

“…In addition, the increase in TNFR2 expression also demonstrated on purified Treg subsets cultured in ascites, further suggests the direct induction of TNFR2 by soluble factors in the ascites in the absence of other immune cells. The ovarian cancer ascites used in our study from patients in advanced disease stages showed a mixture and levels of soluble factors similar to previous studies ( 11 , 18 , 85 , 86 ), with a predominance toward Th2 vs Th1 type cytokines, and high levels of IL-6 and TNF compared to serum. We have consistently observed similar effects across 18 different ovarian cancer ascites and on cells derived from different human volunteers, confirming the robustness of this effect.…”

“…This is because the majority of ovarian cancer patients are diagnosed in late stages, with up to one-third of patients presenting with a prominent peritoneal accumulation of fluid called “ascites.” Ascites development is associated with chemo-resistance, disease recurrence ( 3 , 4 ), and poorer survival in ovarian cancer patients ( 5 – 9 ). Ovarian cancer ascites further contains a complex reservoir of immune cells and cytokines, harboring immunosuppressive cells as well as inflammatory soluble factors ( 7 , 10 , 11 ). This unique milleau has been proposed to help tumor cells evade host immunosurveillance, so that tumor cells can continue growing without restriction ( 3 , 7 , 9 , 10 ).…”

Three-Dimensional Cell Culture Based on Magnetic Fields to Assemble Low-Grade Ovarian Carcinoma Cell Aggregates Containing Lymphocytes

“…Our results showed that cytotoxic cells (NKs and CD8 lymphocytes) were activated, and pointed the T-reg subtype as a long-term persistent lymphocyte present into the cell aggregates, in a sense similar to what have been shown in patients with EOC [51,52].…”

Ascitic Fluid in Ovarian Carcinoma – From Pathophysiology to the Treatment

“…In ascites with malignant cells compared to ascites without malignant cells, CD 107 concentration is lower both with and without direct stimulation by IL 2, due to pronounced immunosuppressive effect of tumor microenvironment. On the other hand, the concentration of local inflammatory factors of TNF and TREG cells is greater in malignant ascites [66].…”