Regression of primary hepatocarcinoma in cancer-prone transgenic mice by local interferon-gamma delivery is associated with macrophages recruitment and nitric oxide production

The clinical potential of tumor therapies must be evaluated using animal mo dels closely resembling human cancers. We investigated the impact of locall y delivered interferon-gamma (IFN-gamma) on primary hepatocarcinoma spontan eously developed by T-SV40 transgenic mice. A single intratumor injection o f adenovirus IFN-gamma was sufficient enough to induce in vivo production o f biologically active IFN-gamma, as assessed by STAT1 activation. IFN-gamma secretion led to the regression of primary tumor, principally by apoptosis of tumor hepatocytes. The lack of T-cells infiltrates in the liver upon tr eatment excluded a role of a specific immune response. In contrast, indirec t pathways may include tumoricidal function of macrophages. Indeed, they we re massively recruited in the entire liver under IFN-gamma treatment; trans migration through hepatic blood Vessels could be observed and co-localizati on with damaged hepatocytes was obvious. This correlated with nonparenchyma l liver cell iNOS expression and high level of NO in hepatic extracts. More over, in vitro experiments showed that NO releasing agents induced cell dea th of freshly isolated tumor hepatocytes, suggesting that NO could be one o f the major effector molecules. Altogether, these observations defined an i mportant role of IFN-gamma in controlling tumor development in a model of p rimary hepatocarcinoma.