TUMOR-INDUCED REGULATION OF SUPPRESSOR MACROPHAGE NITRIC-OXIDE AND TNF-ALPHA PRODUCTION - ROLE OF TUMOR-DERIVED IL-10, TGF-BETA, AND PROSTAGLANDIN E(2)

In vitro-activated macrophages (M phi) co-express cytotoxicity for tumor cells and suppression of lymphocyte proliferation. These M phi functions increase during tumor growth and are mediated by soluble molecules. Because M phi-derived nitric oxide (NO) and TNF-alpha mediate both cytotoxicity and suppression, we determined whether fibrosarcoma (Meth-KDE) growth increased M phi-mediated suppression of T cell proliferation by increasing M phi NO and TNF-alpha production. Tumor-bearing host peritoneal M phi produced more NO and TNF-alpha than normal host M phi when activated with IFN-gamma or LPS, respectively. This tumor-induced increase in M phi NO and TNF-alpha production mediated suppression of alloantigen-driven T cell proliferation, because treatment with either N-G-monomethyl-L-arginine or anti-TNF-alpha Ab blocked tumor-bearing host M phi-mediated suppression. TNF-alpha did not directly suppress T cells, but it induced M phi NO production that down-regulated proliferation. When non-tumor-infiltrating peritoneal M phi were cultured with Meth-KDE cell supernatants, M phi production of NO and TNF-alpha was strongly down-regulated. The tumor-derived molecules responsible for this inhibition were IL-10, TGF-beta(1), and prostaglandin E(2). The experimental evidence leading to this conclusion included: 1) The Meth-KDE cells produced significant levels of these cytokines. 2) Recombinant forms of these cytokines suppressed NO and TNF-alpha production. 3) Ab-mediated absorption of these cytokines from tumor cell supernatants restored NO and TNF-alpha production. 4) Anti-IL-10 and anti-TGF-beta(1), Ab addition to IFN-gamma-stimulated M phi restored NO production. Culture supernatants of two human carcinoma cell lines and another murine fibrosarcoma suppressed M phi NO and TNF-alpha production, which was partly mediated by TGF-beta(1) and prostaglandin E(2). Collectively, these results suggest that tumor growth promotes distal M phi suppressor activity by increasing M phi production of cytotoxic molecules and concomitantly down-regulating the local production of these antitumor molecules.