Mononuclear-cell infiltration in ovarian cancer. III. Suppressor-cell and ADCC activity of macrophages from ascitic and solid ovarian tumours

Abstract

Summary.-Macrophages have been isolated from ascitic and collagenase -dispersed tumours from patients undergoing surgery for ovarian cancer. Macrophages were present in varying proportions in both sites, though the ratio of macrophages to tumour cells was higher in ascites. Marked variation in size (as detected by sedimentation velocity) and cytochemical markers in the macrophages was noted. Highly enriched macrophage fractions were isolated from the ascites and collagenasedispersed solid tumours by a combination of sedimentation velocity and selective EA RFC or adherence techniques. Suppressor activity in the PHA assay was detected in tumour macrophages (4/10 giving>50% inhibition), ascitic macrophages (1/15) and blood monocytes (2/7). Lymphocyte fractions from tumours were unresponsive to PHA and failed to suppress the blood response. Suppressor activity was also present in the purified tumour-cell fraction of 6/14 patients.ADCC activity was tested in a few patients. When the activity was determined against the SB target cells, tumour-derived macrophages were inactive, whereas the ascitic fraction showed low but significant activity which averaged much lower than patient blood values. The ADCC assays carried out with the CRC target cell indicated activity within the range of patient blood values in 4/4 ascites and 2/4 tumour macrophage fractions.Cytotoxicity was also assessed against co-purified autologous tumour cells. Although activity was detected in many of the tests, the results seemed to reflect target cell sensitivity. There appeared to be a correlation between cytotoxicity with test macrophages and normal blood mononuclear cells.The results indicate that the cytochemical heterogeneity and the variation in size between macrophage fractions is associated with a spectrum of activities.WE HAVE INITIATED a study of immune competence of the various inflammatory cell types infiltrating primary solid and ascitic ovarian tumours. In the first paper (Haskill et al., 1982a) we outlined the methods used to isolate these cells and characterized the cell markers associated with infiltrating cells from these tumours. Two classes were characterized; 1 sedimented at < 6 mm/h and was similar in size to most blood mononuclear cells; the other was composed of larger, strongly adherent macrophages distinct from blood monocytes, which sedimented with the tumour cells. In the second communication (Haskill et al. 1982b) we investigated effector-cell functions (PHA, ADCC and NK) associated with blood and bloodequivalent inflammatory cells present in both ascitic and solid tumours. The data indicated that all tumour-derived effector-cell tests were markedly depres-

Evaluation of the interaction of mononuclear phagocytes with ovarian carcinoma cells in a colony assay

“…Freshly isolated ovarian carcinoma cells from different patients were remarkably heterogeneous in their susceptibility to colony inhibition by monocytes. This finding confirms previous data in a [5Cr]-release assay (Haskill et al, 1982) or in a [3H]-thymidine release assay (Mantovani et al, 1980;Peri et al, 1981). Moreover, in one subject monocytes augmented colony formation, an observation in agreement with previous data on the promoting effect of mononuclear phagocytes in ovarian cancer in isotopic or colony assays (Mantovani et al, 1979(Mantovani et al, , 1980Buick et al, 1980).…”

“…Vose & Moore, 1980;Mantovani et al, 1980;Peri et al, 1981;Haskill et al, 1982;Moore et al, 1982;Miner & Nicolson, 1983;Urban & Schreiber, 1983) or with NK cells when fresh non-cultured targets are used (e.g. Introna & Mantovani, 1983 (Mantovani et al, 1980;Haskill et al, 1982 (Todd et al, 1981) and by the virtually complete lack of activity of monocyte-depleted lymphoid cells. As expected, lymphokine supernatants markedly augmented the inhibitory capacity of monocytes on SW626 colony formation.…”

“…On the other hand, cells of the monocytemacrophage series are potent producers of growth factors, that, under certain circumstances, can promote tumour growth in vitro or in vivo (reviewed by Evans, 1979;. Under many conditions, most notably with solid human tumours, the levels of macrophage-mediated killing measured in isotope release assays are relatively low and vary considerably with target cells from different patients (Vose, 1978;Mantovani et al, 1980;Peri et al, 1981;Haskill et al, 1982). It is unclear whether, under these conditions, the induction of increased isotope release by effectors reflects a rapid elimination of effete tumour cells already incapable of self renewal, or actual killing of self renewing clonogenic cells.…”

Expression of MHC products and leucocyte differentiation antigens in gynaecological neoplasms: An immunohistological analysis of the tumour cells and infiltrating leucocytes

“…B73.1+ or Leu 7+ cells were scarcely ever seen, indicating that the OKM1 + population was probably wholly of monocyte/macrophage composition. In ovarian cancer, there is marked size variation and cytochemical heterogeneity among macrophages which is associated with a spectrum of activities from suppression to antibody-dependent cellular cytotoxicity (Haskill et al, 1982b). However, gynaecological cancers, like those of breast, colon and lung (Watanabe et al, 1983;Bhan & Des Marais, 1983;Whitwell et al, 1984;Csiba et al, 1984), contain few cells of natural killer phenotype.…”

Macrophages Mediate Inflammation-Enhanced Metastasis of Ovarian Tumors in Mice

“…Even though the presence of T lymphocytes in ovarian tumors correlates with improved prognosis, T cells in malignant ascites are less likely to be activated than in peripheral blood, suggestive of a local immunosuppressed state (10). Innate immune cells, including macrophages, neutrophils, and NK cells are frequently present in both primary ovarian tumors and malignant ascites (11) and may be important in driving tumor progression. Macrophages can contribute to tumor dissemination by increasing tumor cell adhesion molecules on the peritoneal mesothelium and by releasing growth factors and invasive proteases (12,13).…”