Decreased macrophage‐mediated cytotoxicity in mammary‐tumor‐bearing mice is related to alteration of nitric‐oxide production and/or release

Abstract

Peritoneal-exudate macrophages (PEM) from mammary-tumor-bearing mice have impaired cytotoxic activity against syngeneic and allogeneic tumor targets. The ability of PEM from normal and tumor-bearing mice to bind tumor targets was found to be similar in the presence or the absence of surrogate receptors, which enhanced the binding but not the killing of tumor targets by PEM from tumor-bearing mice, suggesting that other mechanisms are involved in their impaired cytolytic activity. Soluble and membrane-bound TNF-alpha, as well as H2O2, were found in higher amounts in PEM from tumor bearers upon stimulation with LPS, as compared with PEM from normal mice. However, tumor-bearers' macrophages displayed decreased capacity to produce and/or release nitric oxide, which could be reversed by the addition of increasing levels of IFN-gamma. These results indicate that the lack of macrophage cytotoxicity in mammary-tumor-bearing mice is related to impaired production and/or release of NO by these effector cells, possibly aggravated by the insufficient IFN-gamma production previously reported in these animals. Moreover, mammary-tumor progression results in dis-regulation of synthesis of macrophage-mediators, with over-production of molecules to which mammary-tumor cells are insensitive and deficient production of NO, the crucial molecule to which these cells appear to be highly sensitive.

Tumor-induced immune dysfunction: the macrophage connection

“…Our current studies suggest that tumor-derived factors induce increased translocation of the multifunctional transcription factor NF-B in splenic M populations, leading to expression of various cytotoxic effector molecules [McConnell and Elgert, unpublished observations]. Simultaneously in the same host, TAM cytotoxic molecule production is largely abrogated [32,123].…”

Early Block in Maturation Is Associated with Thymic Involution in Mammary Tumor-Bearing Mice

“…Mice bearing the D1-DMBA-3 tumor have increased circulating levels of several known apoptotic mediators (2,(22)(23)(24). Two of these, PGE 2 and TNF-␣, are cytocidal for thymocytes (25)(26)(27).…”

Diminished Expression of Transcription Factors Nuclear Factor κB and CCAAT/Enhancer Binding Protein Underlies a Novel Tumor Evasion Mechanism Affecting Macrophages of Mammary Tumor–Bearing Mice

“…Previous work from our laboratory has shown that, on stimulation with lipopolysaccharide (LPS), thioglycollate-induced peritoneal macrophages (PEM) isolated from BALB/c mice bearing the D1-DMBA-3 mammary tumor display depressed innate immune functions, characterized by diminished macrophage cytotoxicity, low levels of nitric oxide expression, and decreased production of interleukin (IL)-12 (10)(11)(12)(13). In earlier publications, we have shown that the down-regulated production of both IL-12 and inducible nitric oxide synthase (iNOS) is associated with the action of several factors secreted by the mammary tumor used in our studies (12)(13)(14)(15).…”