Identification of an IL-10-producing HLA-DR-negative monocyte subset in the malignant ascites of patients with ovarian carcinoma that inhibits cytokine protein expression and proliferation of autologous T cells.

A newly described subset of monocytes has been identified in peritoneal exudate cells (PEC) from the malignant ascites from patients with ovarian cancer. These cells were characterized by the production of IL-10 and TGF-beta2, but not IL-12, IL-1alpha, or TNF-alpha, and they expressed CD14, CD16, and CD54, but not HLA-DR, CD80, CD86, CD11a, CD11b, or CD25 cell surface Ags. Since this subset of monocytes could affect the modulation of tumor immune responses in vivo, studies were undertaken to determine their effect on the activation and proliferation of autologous T cells from the peritoneal cavity of patients with ovarian carcinoma. Expression of cytokine-specific transcripts in T cells was determined by RT-PCR. Transcripts for the following cytokines were detected in patient specimens that also contained the IL-10-producing monocytes IL-2 (12 of 17 specimens), GM-CSF (9 of 17 specimens), IFN-gamma (6 of 17 specimens), and TNF-alpha (4 of 17 specimens). Cytokine production by T cells was determined by intracellular flow cytometry and by ELISA. IL-2 and IFN-gamma proteins, unlike their transcripts, were detected only in specimens that lacked IL-10-producing monocytes. IL-10-producing monocytes cocultured with autologous T cells inhibited the proliferation of the T cells in response to PHA. However, T cells cocultured with PEC from which the IL-10-producing monocytes had been removed did not inhibit T cell proliferation. Moreover, the inhibition of T cell proliferation by IL-10-producing monocytes could be reversed by adding neutralizing Abs to both IL-10R and TGF-beta2. These results suggest that this subset of monocytes may modulate immune responses by inhibiting T cell proliferation and cytokine protein production.

In vitro growth inhibition of ovarian cancer cells by decorin: synergism of action between decorin and carboplatin.

In vitro studies showed that decorin, a small proteoglycan that is a normal component of the cell matrix involved in tissue scaffolding, effectively inhibited the growth of two ovarian cancer lines, SKOV3 and 2774. Using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay to measure cell growth, IC50s for decorin ranged from 150 to 400 microg/ml for the two cell lines. In contrast, the growth of tumor cells grown on an artificial cell matrix (Matrigel) was unaffected by decorin treatment, perhaps because of the decorin being irreversibly bound by matrix-associated collagen. Decorin-induced inhibition of ovarian tumor cells appeared to be associated with the increased expression of the cyclin-dependent kinase inhibitor p21Waf1/Cip1. Up-regulation of p21 expression was shown by Western blot analysis in decorin-treated ovarian cancer cells. No decorin-induced up-regulation of c-myc was seen, although decorin was reported to activate the epidermal growth factor receptor. Decorin was also shown to synergize with carboplatin to inhibit the growth of ovarian tumor cells. Additional studies are warranted to determine the role of decorin in the treatment of ovarian cancer.