A ROLE FOR TUMOR-NECROSIS-FACTOR IN POLY(I-C)-INDUCED HEMORRHAGIC NECROSIS AND T-CELL-DEPENDENT REGRESSION OF A MURINE SARCOMA

It was found that intravenous injection of the synthetic double-stranded ribonucleic acid, polyinosinic-polycytidylic acid [poly(I:C)], which is a well-studied interferon (IFN)-inducing agent, can result in extensive hemorrhagic necrosis of the center of an established murine sarcoma and in subsequent complete regression of the surviving rim of the tumor. The poly(I:C)-induced intratumor hemorrhagic reaction was associated with production of appreciable quantities of tumor necrosis factor (TNF) by the host. Neutralization of TNF by treatment with anti-rTNF immunoglobulin G (IgG) caused substantial inhibition of hemorrhagic necrosis and prevented tumor regression from proceeding. Tumor regression was prevented in all mice by depleting them of CD8+ T cells 1 day before poly(I:C) was given. Taken as a whole, the results indicate that the antitumor action of poly(I:C), like that of endotoxin, is based on its capacity to induce the host to make enough TNF to cause a hemorrhagic reaction extensive enough to reduce the tumor burden to a size capable of being dealt with by an underlying host antitumor immune response.