Suppression of high affinity IL-2 receptors on mitogen activated lymphocytes by glioma-derived suppressor factor

Abstract

Previously we have reported that human glial tumor cells secrete a factor(s) which suppresses the mitogen responsiveness of normal human peripheral blood lymphocytes (PBL) in a dose dependent manner. In this study we extend these observations and explore the possible mechanisms by which glioma-derived suppressor factor(s) (GSF) modulates lymphocyte reactivity. Preincubation of lymphocytes with GSF for 2 hrs induces suppression of lymphocyte mitogen responsiveness. GSF also inhibits production of interleukin-2 (IL-2) by mitogen activated human T-cells. Addition of delectinated or recombinant IL-2 to mitogen activated human T-cells in the presence of GSF does not restore the normal proliferative response of these cells. These findings suggest that GSF induces a defect in the expression of the receptor for IL-2 (IL-2R) on activated T-cells. Binding studies with radiolabeled IL-2 demonstrated that GSF suppresses and in some cases completely inhibits the expression of functional high affinity IL-2R on activated T-cells, thereby, preventing association of IL-2R with its receptor and the subsequent progression of the cell into the proliferative stage of the cell cycle. These cellular defects induced by GSF closely parallel the observed defects noted in T-cells obtained from patients with gliomas, indicating that the factors elicited from glial tumors may be responsible for the immunological deficits observed in patients with primary malignant intracranial tumors.

Differential Effects of IL-2 and IL-15 on Expression of IL-2 Receptor α

“…In addition T lymphocytes from patients with glioma tumors when stimulated by an antigen or a mitogen remain negative for IL-2R␣ cell surface expression in situations where IL-2R␣ mRNA and protein are present within the cells. The production of TGF␤ 2 by tumor cells appears to be responsible for this effect (24,34,35). The same situation was observed with a subset of Hairy Cell Leukemia cells that express the IL-2R␣ intracellularly but are negative for its surface expression (36).…”

Role of Cytokines in the Regulation of Glioma Tumour Growth and Angiogenesis

“…In addition, tumour cyst fluid and cerebral spinal fluid from glioma patients suppressed the mitogen responsiveness of normal lymphocytes [59] . Further support for the secretion of suppressive factors by gliomas comes from the observation that glioma cell culture supernatants (GCS; freshly explanted or from tumour cell line) inhibit the function of T-cells obtained from normal individuals [60] Taken together, these observations confirm that gliomas actively synthesize and secrete potent immunoregulatory moieties capable of inhibiting T-cell responsiveness. These factors are presented in Table 1.…”

“…At present, not all of the moieties within GCS that are of an immunosuppressive nature have been fully characterized. This is exemplified by the observation that the factors inhibiting proliferative T-cell responses do not appear to be the same as those capable of altering monocyte cytokine secretion patterns [60] . In addition, some of the activity in GCS which affects the immune functioning of monocytes and T-cells can be reversed with neutralizing antibodies (i.e., anti-IL-10 mAb or inhibitors (e.g., the PGE inhibitors, 2 naproxen, ibuprofen and indomethacin) [61].…”

Factors, including transforming growth factor β, released in the glioblastoma residual cavity, impair activity of adherent lymphokine-activated killer cells

“…Of note are recent studies that correlate these immunological dysfunctions with the production of immunosuppressire mediators by gliomas [27]. In fact, these neoplasms have been shown in vitro to produce factor(s), including TGF[~, that inhibit a variety of lymphocyte functions [1,3,4,6,14,15,16,29,32,33]. Whatever its source, TGF[3 can inhibit IL-2-induced T cell proliferation [6,13], cytotoxic T cell generation [7,20,23], production of tumour-infiltrating lymphocytes (TIL) [25] and the generation of LAK cells [14,20].…”