Inhibition of lymphocyte function by glioblastoma-derived transforming growth factor β2

Abstract

Human glioblastoma cells secrete an inhibitory factor termed "glioblastoma-derived T-cell suppressor factor" (G-TsF). A member of the transforming growth factor beta (TGF beta) family, G-TsF is identical to TGF beta 2. The present study investigated the effect of G-TsF/TGF beta 2 on the proliferative and cytotoxic properties of tumor-infiltrating lymphocytes (TIL's) isolated from malignant gliomas after expansion in vitro with interleukin-2 (IL-2). The results demonstrate that the IL-2 (5 to 20 U/ml)-dependent proliferative response of glioma-derived TIL's was inhibited 70% to 85% by G-TsF/TGF beta 2 and that the inhibitory effect could be reduced by using increasing concentrations of IL-2 (100 to 200 U/ml). Tumor necrosis factor alpha (TNF alpha) enhanced the IL-2-dependent proliferation of TIL's cultured in low concentrations of IL-2 (10 U/ml); however, neither TNF alpha nor interferon gamma was able to reduce the inhibitory effect of TGF beta 2 on TIL proliferation. In addition, TGF beta 2 suppressed 60% to 100% the cytotoxic response of glioma-derived TIL's against several tumor targets, including autologous glioma cells, and the suppressive effect was shown to be reduced by increasing concentrations of IL-2.

Downregulation of major histocompatibility complex antigens in invading glioma cells: stealth invasion of the brain

“…Glioma-mediated immunosuppression and downregulation of the host immune response has been associated with the release of immunosuppressive factors by glioma cells, for example, transforming growth factor (TGF)-b1, b2, and b3. [32][33][34][35][36][37][38] In addition to TGF-b, other factors capable of inhibiting immune function 37 include the cytokines interleukin (IL)-6 and IL-10, [39][40][41][42][43][44][45] prostaglandin E, [46][47][48][49][50] and gangliosides. 51 TGF-b1 and IL-10 act by suppressing T cell function.…”

Cytokine gene therapy of gliomas: effective induction of therapeutic immunity to intracranial tumors by peripheral immunization with interleukin-4 transduced glioma cells

“…For instance, gliomas release factors such as transforming growth factor-beta (TGF-␤), which inhibit a number of functions of cytolytic T cells and NK cells. 10,11 Gliomas also express Fas ligand (CD95L), which induces apoptosis in immune effector cells. 12 A more recent study has demonstrated that human glioma cells produce substances that also suppress the function of antigen presenting cells (APCs).…”

Rescuing defective tumor-infiltrating T-cell proliferation in glioblastoma patients

“…GBM patients are profoundly immunosuppressive, both locally within the tumor and systemically (12). Multiple mechanisms exist to suppress effective immune responses targeted toward the tumor, including the blood-brain barrier that restricts lymphocyte trafficking (13), the local production of immunosuppressive cytokine transforming growth factor β (14,15), the increased expression of B7-H1 in glioma and the induction of T-cell apoptosis (16,17), the increased frequency of circulating regulatory T cells (18) and defective T-cell priming by microglial cells (19). On the other hand, stronger immune responses are associated with lower glioma incidences and/or increased survival.…”