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

Abstract

Adherent lymphokine-activated killer (A-LAK) cells were obtained from peripheral blood lymphocytes of patients with recurrent glioblastoma. In vitro features of A-LAK cultures were assessed in comparison to those of non-adherent lymphokine-activated killer (NA-LAK) cells of the same patients with regard to cytotoxic activity, proliferation and surface markers. Only in a minority of cases did A-LAK cells show a markedly higher cytotoxicity on K562, Daudi and allogeneic glioblastoma cells. Nevertheless, A-LAK cells proliferated significantly better than NA-LAK and contained higher percentages of CD16+, CD56+ and CD25+ cells, indicating that A-LAK cells from these patients represent a subpopulation of lymphocytes enriched for activated natural killer cells. We also investigated whether immunosuppressive factor(s) were present in the tumour bed of recurrent gliomas. To this end, samples of glioblastoma cavity fluid (GCF), which accumulates in the cavity of subtotally removed tumour, were recovered and tested for the presence of immunosuppressive activity. All GCF samples analysed were shown to inhibit in vitro proliferation and antitumour cytotoxicity of 1-week-cultured A-LAK cells in a dose-dependent manner. Such GCF activity was effectively antagonized by a transforming growth factor beta (TGF beta) neutralizing antibody, indicating the involvement of TGF beta in lymphocyte inhibition. These results show that in the tumour cavity remaining after subtotal glioblastoma resection a marked immunosuppressive activity, probably due to local release of TGF beta, is present; such activity may negatively influence the therapeutic effectiveness of local cellular immunotherapy.

Second Generation Tyrosine Kinase Inhibitors Combined With Allogeneic Hematopoietic Stem Cell Transplantation Improve the Prognosis of Patients with Chronic Myelogenous Leukemia in Blast Crisis

“…A mechanism has been proposed to account for antitumor T-cell and NKcell dysfunction: secretion of suppressive factors such as transforming growth factor β1 [14,15] and interleukin 10 [16], in the leukemia microenvironment. Thus, for a lower leukemia burden, the GVL effect will be greater due to the less stringent downregulation of the antitumor T-cell immune response mediated by the decreased secretion of suppressive factors.…”

Transforming growth factor-beta: A target for cancer therapy

“…Tumor cell lines modified to express TGF-β have been shown to elicit much weaker cytotoxic T-lymphocyte (CTL) responses compared to unmodified cell lines (Mule et al, 1988). In part, this is because TGF-β inhibits the expression of the high affinity IL-2 receptor by T-lymphocytes, leading to inhibition of CTL activation (Ruffini et al, 1993). In addition, TGF-β2 is able to direct the development of naïve T-lymphocytes into regulatory T-lymphocytes (T regs ) by induction of the transcription factor FOXP3 .…”

Inmunoterapia en astrocitomas de alto grado: principios y estado actual

“…Por esta razón, numerosos investigadores han centrado sus esfuerzos en el bloqueo de los factores tumorales responsables de dicha inmunosupresión. Se ha demostrado que el bloqueo mediante células T específicas 30 , anticuerpos monoclonales 89 o mediante sustancias específicas como la decorina 72,95 puede potenciar la respuesta y erradicar los tumores en animales de experimentación. Además, se ha demostrado que la manipulación local del microambiente tumoral mediante la disminución de la concentración de TGF-β potencia la función citolítica de los linfocitos peritumorales 60 .…”