CONTRIBUTION OF THE CXC CHEMOKINES IF-10 AND MIG TO THE ANTITUMOR EFFECTS OF IL-12

The mechanisms by which interleukin-12 (IL-12) exerts antitumor effect s have been difficult to dissect. In this study, we examined the poten tial contribution of the chemokines interferon-gamma-inducible protein -10 (IP-10) and Mig to the antitumor effects of IL-12. Using an athymi c mouse model, local inoculations with IL-12 consistently produced tum or size reductions associated with characteristic tumor necrosis and v ascular damage. These effects were indistinguishable from those produc ed by IF-10 or Mg injected locally in the same tumor model. Local and systemic treatment with IL-12 was associated with expression of the in terferon-gamma (IFN-gamma), IP-10, and Mig genes and proteins in the t umor. Levels of IF-10 and Mig expression in the tumor; the liver, and the kidney were inversely correlated with tumor size. Administration i n vivo of neutralizing antibodies to IF-10 and Mig reduced substantial ly the antitumor effects of IL-12 inoculated locally into the tumors. These results support the notion that IF-10 and Mig contribute to the antitumor effects of IL-12 through their inhibitory effects on tumor v asculature.