THE ALTERED TUMORICIDAL CAPACITY OF MACROPHAGES ISOLATED FROM TUMOR-BEARING MICE IS RELATED TO REDUCED EXPRESSION OF THE INDUCIBLE NITRIC-OXIDE SYNTHASE GENE

Nitric oxide (NO) is a major effector molecule in the destruction of t umor cells by activated macrophages. However, in many cases, developin g neoplasms appear to be capable of impairing steps in the complex pro cess leading to NO production as a means of avoiding immune destructio n. After activation with lipopolysaccharide (LPS), peritoneal-elicited macrophages (PEM) from mice bearing mammary tumors display alteration s in their ability to lyse tumor cells due to reduced production of NO . In contrast, when these same cells are stimulated with LPS in combin ation with interferon gamma (IFN-gamma), they are able to produce NO a nd lyse targets at normal levels. Since tumor-associated macrophages a re intimately associated with the cells of the developing tumor, their ability to produce NO and lyse tumor targets is likely to be more rel evant to controlling tumor growth. This population of macrophages exhi bited a more profound inability to produce NO and lyse targets and, un like the PEM, was not able to upregulate these functions even when tre ated with combinations of LPS and IFN-gamma. Northern and Western blot s revealed that inducible nitric oxide synthase (iNOS) mRNA and protei n levels correlated directly with the ability of each macrophage popul ation to produce NO, and the levels of these macromolecules were alter ed sufficiently in tumor bearers' macrophages to account for the dimin ished NO production described. These results indicate that a spatial g radient of suppression of macrophage cytolytic activity and iNOS expre ssion exists in mammary tumor-bearing mice, whereby macrophage from wi thin the turner exhibit a more pronounced suppression than the more di stally located PEM. This suppression may be due to proximity of the ma crophages to the developing tumor, macrophage maturational state, or b oth.