The enzyme indoleamine 2,3-dioxygenase (IDO) is emerging as a facilitator of cancer development through its effects on cancer-associated inflammation. Recent studies report a significant improvement of the response rates in melanoma patients to PD-1 antibodies when IDO inhibitors were added to the regimen. Data on IDO expression in primary human melanomas are, however, incomplete and conflicting. Here, we show that the level of IDO expression in primary human melanoma cells significantly correlates with Breslow thickness (P = 0.003), the presence of tumor-infiltrating lymphocytes (P = 0.029), and the intensity of the peritumoral inflammatory infiltrate (P = 0.001). The expression of IDO in melanoma cells predicted independently of Breslow thickness and tumor stage (P = 0.04). We further show that CD11c dendritic cells and CD68 macrophages in the microenvironment of melanomas express IDO. The level of IDO expression in antigen-presenting cells correlated positively to peritumoral inflammation (P = 0.001) but not to tumor-infiltrating lymphocytes. Significant negative correlation with progression-free survival was found for patients for whom antigen-presenting cells were very strongly IDO positive. These results suggest that IDO induction within melanoma cells may directly reflect tumor progression, whereas IDO in antigen-presenting cells may determine immune surveillance with impact on local and systemic tolerance.
The sulfonated shale oil extract, Ichthyol, was studied for its effect on the migration of human neutrophilic granulocytes by the Boyden chamber technique. When presented to the cells in a concentration gradient, Ichthyol induced a directed migration. There was little or no chemokinetic effect of Ichthyol when added to the cell compartment of the Boyden chamber. The chemotactic migration towards the tripeptides, formyl-methionyl-leucyl-phenylalanine and formyl-norleucyl-leucyl-phenylalanine, towards the arachidonic acid-derived eosinophil chemotactic factor released from neutrophils by the ionophore A 23187, and towards complement-derived chemotactic activity of normal human serum was inhibited or abrogated by Ichthyol. The Ichthyol effect on f-MLP chemotaxis could be partly overcome by excessive f-MLP concentrations. It was reversible when Ichthyol-incubated cells were washed and resuspended in regular buffer. It is suggested that various substances contained in Ichthyol interacted with either the chemotactic factors or the cell membrane or both and thus blocked cell stimulation. The results could help to explain the cell accumulation and abscess formation observed with Ichthyol in inflammatory skin lesions and the anti-inflammatory properties of the drug.
Sulfonated shale oils (ammonium bituminosulfonate, ichthammol, Ichthyol), shown previously to induce the directed migration of human neutrophils in Boyden chambers and to inhibit the directed migration towards the chemotactic factors C5a, LTB4, and f-Met-Leu-Phe, were studied for their effect on other neutrophil functions, which are stimulated by chemotactic factors. Like other chemotactic factors ammonium bituminosulfonate increased the adherence of neutrophils to nylon fibers, but it did not induce the release of the primary granule enzyme glucosaminidase from cytochalasin B-treated cells and it did not stimulate the production of oxygen radicals as measured by lucigenin-dependent chemiluminescence if studied under nontoxic conditions. When added together with the chemotactic tripeptide f-Met-Leu-Phe, ammonium bituminosulfonate inhibited adherence augmentation, enzyme release, and oxygen-radical production induced by the chemotactic factor. The results indicate that ammonium bituminosulfonate not only inhibited chemotactic migration but the whole spectrum of neutrophil functions induced by a chemotactic factor.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.