Tumor-infiltrating macrophages induce apoptosis in activated CD8(+) T cells by a mechanism requiring cell contact and mediated by both the cell-associated form of TNF and nitric oxide

We have investigated the ability of different cells present in murine tumor s to induce apoptosis of activated CD8(+) T cells in vitro. Tumor cells do not induce apoptosis of T cells; however, macrophages that infiltrate tumor s are potent inducers of apoptosis. Tumor macrophages express cell surface- associated TNF, TNF type I (CD120a) and II (CD120b) receptors, and, upon co ntact with T cells which induces release of IFN-gamma from T cells, secrete nitric oxide. Killing of T cells in vitro is blocked by Abs to IFN-gamma, TNF, CD120a, or CD120b, or N-methyl-L-arginine. In concert with that findin g, tumor macrophages isolated from either TNF type I or type II receptor -/ - mice are not proapoptotic and do not produce nitric oxide upon contact wi th activated T cells. Control macrophages do not express TNF receptors or r elease nitric oxide. Tumor cells or tumor-derived macrophages do not expres s FasL, and blocking Abs to either Fas or FasL have no effect on macrophage -mediated T cell killing. These results demonstrate that macrophages which infiltrate tumors are highly proapoptotic and may be responsible for elimin ation of activated antitumor T cells within the tumor bed.