Sensitivity of tumoricidal function in macrophages from different anatomical sites of cancer patients to modulation of arachidonic acid metabolism.

The sensitivity of cancer patient macrophages from different anatomical sites to arachidonic acid metabolism was investigated in tumor cell cytotoxicity assays. Alveolar macrophages and peripheral blood monocytes from 13 non-small cell lung cancer patients, peritoneal macrophages and peripheral blood monocytes from 13 ovarian cancer patients, and comparable macrophages from control patients with nonmalignant lung or gynecological diseases were tested. Inhibitors of either the cyclooxygenase pathway or the lipoxygenase pathway together with specific metabolites of each pathway were used to evaluate how these different macrophage populations are regulated by eicosanoids. In addition, metabolic studies were performed to compare directly the arachidonic acid metabolism of macrophages obtained from these different anatomical locations. The results demonstrate that the peripheral blood monocytes from lung cancer and ovarian cancer patients and the peritoneal macrophages from ovarian cancer patients are sensitive to cyclooxygenase inhibition; this was not seen with comparable macrophages from the relevant control patients. Sensitivity to modulation by cyclooxygenase inhibition correlated with increased cyclooxygenase metabolism and with the capacity of prostaglandin to mediate suppression of tumoricidal function in these populations of cancer patient macrophages. In contrast, alveolar macrophages from cancer patients were not sensitive to either cyclooxygenase inhibition or to prostaglandin-mediated suppression. No such differential influences were revealed for the lipoxygenase pathway of arachidonic acid metabolism in any macrophage population tested. Thus, eicosanoids, particularly those of the cyclooxygenase pathway, can be a critical immunoregulatory feature of certain tumor microenvironments.