NITRIC-OXIDE INVOLVEMENT IN TUMOR-INDUCED IMMUNOSUPPRESSION

The mechanisms of immunosuppression induced by colon cancer in rats we re investigated at the systemic and tumor levels. During tumor growth (after i.p. injection of rat colon adenocarcinoma cells in syngeneic B D IX rats), Con A-induced proliferation of splenic mononuclear cells d ecreased and nitric oxide (NO) production by splenic macrophages incre ased concomitantly. Incubating splenic mononuclear cells with an inhib itor of NO synthase, N-G-monomethyl-L-arginine, restored lymphocyte pr oliferation. A low level of inducible NO synthase mRNA was detectable in tumors by Northern blotting, with a weak increase during tumor grow th. The NO concentration measured in the tumor nodules increased weakl y parallel to the tumor growth. Five and six weeks after tumor cell in jection, tumor-infiltrating lymphocytes from disaggregated tumors did not proliferate in the presence of Con A. Addition of N-G-monomethyl-L -arginine inhibited the production of NO in tumor dissociations and en hanced tumor-infiltrating lymphocyte proliferation. Glyceryl trinitrat e (a NO-releasing compound) totally inhibited the lymphocyte prolifera tion in vitro while it slightly reduced the tumor cell proliferation. T lymphocytes were therefore more sensitive to NO than were tumor cell s. Culture medium from tumor cells induced NO production by splenic ma crophages, although the factor involved has not yet been identified. F urthermore, tumor cells could also play a part in NO production by tum ors because the tumor cells were induced to produce NO by IFN-gamma pl us IL-1. These results strongly suggest the participation of NO in the tumor-induced immunosuppression in rats.