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

Abstract

Interferon-gamma (IFNγ) and tumor necrosis factor-alpha (TNFα) 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 IFNγ and TNFα gene transfer in glioma-bearing rodents. Survival was prolonged in mice treated with AdmIFNγ or AdTNFα compared to AdLacZ- and saline-inoculated controls, and AdmIFNγ- or AdTNFα-treated animals revealed significantly smaller tumors. These effects were accompanied by significant up-regulation of tumor MHC-I expression in AdmIFNγ-inoculated animals, and of MHC-II in AdTNFα-treated tumors. Significantly enhanced intratumoral infiltration with CD4⁺ and CD8⁺ T cells was visible in animals treated with AdmIFNγ, AdTNFα, or a combination of AdmIFNγ and AdTNFα. In addition, AdTNFα 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 IFNγ and TNFα gene transfer as a treatment strategy for glioma and illustrate possible physiological pathways responsible for the therapeutic benefit observed.