Ectopic expression of the proteoglycan, decorin, abrogates the growth of experimental C6 gliomas in the rat. Since gliomas release large amounts of transforming growth factor-beta (TGF-beta) and since decorin is a TGF-beta antagonist, decorin gene transfer-mediated abrogation of glioma growth in vivo may involve enhanced immunogenicity of the tumor cells. Here, we report that human glioma cells stimulate alloreactive immune responses when engineered to express decorin whereas parental glioma cells are non-immunogenic in vitro. The alloreactive immune response is mediated by CD8+ and CD4+ T cells as well as by NK cells. The immunosuppression exerted by parental or mock-transfected glioma cells is mediated by soluble factors and can in part be mimicked by exogenous TGF-beta. However, neutralizing anti-TGF-beta antibodies do not reverse glioma-mediated immunosuppression, suggesting that decorin abrogates glioma-induced immune cell inhibition by interfering with the activity of other, so far unidentified glioma-secreted mediators. We conclude that enhanced immunogenicity may mediate the antineoplastic effects of decorin gene therapy for malignant glioma but that factors other than TGF-beta may be responsible for glioma-induced immunosuppression.