Monocyte/macrophage and T-cell infiltrates in peritoneum of patients with ovarian cancer or benign pelvic disease

BACKGROUND: We previously showed that tumor-free peritoneum of patients with epithelial ovarian cancer (EOC) exhibited enhanced expression of several inflammatory response genes compared to peritoneum of benign disease. Here, we examined peritoneal inflammatory cell patterns to determine their concordance with selected enhanced genes. METHODS: Expression patterns of selected inflammatory genes were mined from our previously published data base. Bilateral pelvic peritoneal and subjacent stromal specimens were obtained from 20 women with EOC and 7 women with benign pelvic conditions. Sections were first stained by indirect immunoperoxidase and numbers of monocytes/macrophages (MO/MA), T cells, B cells, and NK cells counted. Proportions of CD68+ cells and CD3+ cells that coexpressed MO/MA differentiation factors (CD163, CCR1, CXCR8, VCAM1, and phosphorylated cytosolic phospholipase A(2 )[pcPLA(2)]), which had demonstrated expression in EOC peritoneal samples, were determined by multicolor immunofluorescence. RESULTS: MO/MA were present on both sides of the pelvic peritoneum in EOC patients, with infiltration of the subjacent stroma and mesothelium. CD68+ MO/MA, the most commonly represented population, and CD3+ T cells were present more often in EOC than in benign pelvic tumors. NK cells, B cells, and granulocytes were rare. CXCL8 (IL-8) and the chemokine receptor CCR1 were coexpressed more frequently on MO/MA than on CD3+ cells contrasting with CD68+/CD163+ cells that coexpressed CXCL8 less often. An important activated enzyme in the eicosanoid pathway, pcPLA(2), was highly expressed on both CD68+ and CD163+ cells. The adherence molecule Vascular Cell Adhesion Molecule-1 (VCAM1) was expressed on CD31+ endothelial cells and on a proportion of CD68+ MO/MA but rarely on CD3+ cells. CONCLUSION: The pelvic peritoneum in EOC exhibits a general pattern of chronic inflammation, represented primarily by differentiated MO/MA, and distinct from that in benign conditions concordant with previous profiling results

Cytokines, GM-CSF and IFNγ administered by priming and post-chemotherapy cycling in recurrent ovarian cancer patients receiving carboplatin

BACKGROUND: Monocyte/macrophages (MO/MA), a polymorphic population of innate immune cells, have the potential to mediate antitumor effects, and may also contribute to protumor effects. A priming and post-chemotherapy schedule of the myeloid cell mobilizing and immune stimulatory growth factor, granulocyte monocyte stimulating factor (GM-CSF, Leukine(®)) and the MO/MA activating cytokine recombinant interferon gamma 1b (rIFN-γ1b, Actimmune(®)) has been developed. The pre- and post-chemotherapy design is based upon known in vivo kinetics and immune modulatory effects of these molecules. Carboplatin (Paraplatin(®)) was selected as the cornerstone of treatment of epithelial ovarian cancer (EOC). METHODS: We studied hematopoietic and immunologic effects of GM-CSF and rIFN-γ1b before and after carboplatin in patients with recurrent EOC. Potentially chemotherapy-sensitive patients with recurrent measurable tumors received subcutaneous GM-CSF (starting at 400 μg/day) for 7 days plus subcutaneous rIFN-γ1b (100 μg) on days 5 and 7, before and after intravenous carboplatin (area under the curve of 5). We performed standard hematologic assessment and monitored monocyte (MO), dendritic cell, major cell subset counts, and antibody-dependent cell-mediated cytotoxicity (ADCC) against a Her2neu(+ )tumor cell line, as well as selected plasma inflammatory cytokine, chemokine and growth factor levels. RESULTS: Our analysis comprised only the first 3 months of treatment in the initial 25 patients. Relative to pretreatment baseline values, white blood cell, neutrophil, MO, and eosinophil counts increased (P ≤ .001 for each); the proportion of platelets increased 9 days after the second (P ≤ .002) and third (P ≤ .04) carboplatin treatments; and the number of cells in the activated MO subsets CD14+HLA-DR+, CD14+CD64+, and CD14(+)CXCR3(+ )increased (P ≤ .04 for each); plasma levels of the proangiogenic interleukins 1α, 6, and 8 were lower (P ≤ .03 for each); M-CSF, a product of activated MO/MA, was increased on day 9 (P = .007); and GM-CSF was increased in plasma after GM-CSF administration (P ≤ .04). Quality of life measurements were reduced during the GM-CSF/IFN-γ1b cycle while recovering at pre-chemotherapy baseline for FACT-G scores only. CONCLUSION: A novel regimen of GM-CSF plus IFN-γ1b administered to 25 EOC patients receiving carboplatin increased myeloid cells, platelets and total activated MO populations during the initial 3 months; however, ADCC responses were not consistently enhanced during this period