Treatment of intracranial glioma with in situ interferon-gamma and tumor necrosis factor-alpha gene transfer

Abstract

Interferon-gamma (IFNgamma) and tumor necrosis factor-alpha (TNFalpha) are potent immunostimulatory cytokines with demonstrated tumoricidal effects in a variety of cancers. With the aim of investigating their ability to generate antitumor immune responses in malignant brain tumors, we describe the use of in situ adenoviral-mediated IFNgamma and TNFalpha gene transfer in glioma-bearing rodents. Survival was prolonged in mice treated with AdmIFNgamma or AdTNFalpha compared to AdLacZ- and saline-inoculated controls, and AdmIFNgamma- or AdTNFalpha-treated animals revealed significantly smaller tumors. These effects were accompanied by significant up-regulation of tumor MHC-I expression in AdmIFNgamma-inoculated animals, and of MHC-II in AdTNFalpha-treated tumors. Significantly enhanced intratumoral infiltration with CD4(+) and CD8(+) T cells was visible in animals treated with AdmIFNgamma, AdTNFalpha, or a combination of AdmIFNgamma and AdTNFalpha. In addition, AdTNFalpha therapy down-regulated the expression of endothelial Fas ligand, a cell membrane protein implicated as a contributor to immune privilege in cancer. These findings demonstrate the effectiveness of local IFNgamma and TNFalpha gene transfer as a treatment strategy for glioma and illustrate possible physiological pathways responsible for the therapeutic benefit observed.