The failure of current immunotherapy for malignant glioma. Tumor-derived TGF-β, T-cell apoptosis, and the immune privilege of the brain

Abstract

Human malignant gliomas are rather resistant to all current therapeutic approaches including surgery, radiotherapy and chemotherapy as well as antibody-guided or cellular immunotherapy. The immunotherapy of malignant glioma has attracted interest because of the immunosuppressed state of malignant glioma patients which resides mainly in the T-cell compartment. This T-cell suppression has been attributed to the release by the glioma cells of immunosuppressive factors like transforming growth factor-β (TGF-β) and prostaglandins. TGF-β has multiple effects in the immune system, most of which are inhibitory. TGF-β appears to control downstream elements of various cellular activation cascades and regulates the expression of genes that are essential for cell cycle progression and mitosis. Since TGF-β-mediated growth arrest of T-cell lines results in their apoptosis in vitro, glioma-derived TGF-β may prevent immune-mediated glioma cell elimination by inducing apoptosis of tumor-infiltrating lymphocytes in vivo. T-cell apoptosis in the brain may be augmented by the absence of professional antigen-presenting cells and of appropriate costimulating signals. Numerous in vitro studies predict that tumor-derived TGF-β will incapacitate in vitro-expanded and locally administered lymphokine-activated killer cells (LAK-cells) or tumor-infiltrating lymphocytes. Thus, TGF-β may be partly responsible for the failure of current adoptive cellular immunotherapy of malignant glioma. Recent experimental in vivo studies on non-glial tumors have corroborated that neutralization of tumor-derived TGF-β activity may facilitate immune-mediated tumor rejection. Current efforts to improve the efficacy of immunotherapy for malignant glioma include various strategies to enhance the immunogenicity of glioma cells and the cytotoxic activity of immune effector cells, e.g., by cytokine gene transfer. Future strategies of cellular immunotherapy for malignant glioma will have to focus on rendering glioma cell-targeting immune cells resistent to local inactivation and apoptosis which may be induced by TGF-β and other immunosuppressive molecules at the site of neoplastic growth. Cytotoxic effectors targeting Fas/APO-1, the receptor protein for perforin-independent cytotoxic T-cell killing, might be promising, since Fas/APO-1 is expressed by glioma cells but not by untransformed brain cells, and since Fas/APO-1-mediated killing in vitro is not inhibited by TGF-β.