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Influence of PGE2- and cAMP-modulating agents on human glioblastoma cell killing by interleukin-2-activated
M C Kuppner1, Y Sawamura, M F Hamou
1Department of Neurosurgery, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Abstract:
Human glioblastoma cells secrete factors, such as prostaglandin E (PGE) and transforming growth factor beta type 2, which are capable of suppressing several immune functions. The present study investigated the effect of PGE2 and agents known to increase intracellular cyclic adenosine monophosphate (cAMP) levels on 1) the induction of lymphokine-activated killer (LAK) cell activity from the peripheral blood lymphocytes (PBL) of both normal and glioma patients and on 2) the cytolytic activities of tumor-infiltrating lymphocytes (TIL's) isolated from malignant gliomas after expansion in vitro with interleukin-2 (IL-2). Cytolytic activity was measured against autologous and allogeneic tumor cells and the natural killer-resistant Daudi cell line. The results demonstrate that PGE2 and agents known to increase intracellular cAMP levels can significantly suppress the IL-2-dependent generation of cytolytic activity from the PBL of normal and glioma patients and from glioblastoma-derived TIL's. The inhibitory effects of these agents could not be reduced by higher concentrations of IL-2 or by cyclic guanosine monophosphate. Although the suppressive effect of PGE2 was most significant during the early stages of LAK cell generation, an inhibitory effect was still evident when PGE2 was added directly to the cytotoxicity assay. Secretion of PGE2 by glioblastoma cells in vivo may regulate both the generation of an immune response and the effectiveness of adoptively transferred immune cells.
Insights
Prostaglandin E2 (PGE2) and agents increasing cyclic adenosine monophosphate (cAMP) suppress immune cell activity. This hinders the generation of lymphokine-activated killer (LAK) cells and tumor-infiltrating lymphocytes (TILs) in glioblastoma patients.
Area of Science:
- Immunology
- Cancer Biology
- Molecular Biology
Background:
- Glioblastoma cells release immune-suppressing factors like prostaglandin E (PGE) and transforming growth factor beta type 2.
- These factors can inhibit crucial immune functions, potentially aiding tumor evasion.
Purpose of the Study:
- To investigate the impact of PGE2 and cyclic adenosine monophosphate (cAMP)-elevating agents on immune cell activity.
- To assess the effects on lymphokine-activated killer (LAK) cell induction from peripheral blood lymphocytes (PBL) and tumor-infiltrating lymphocytes (TILs) in glioblastoma patients.
Main Methods:
- Cultured peripheral blood lymphocytes (PBL) and tumor-infiltrating lymphocytes (TILs) from normal donors and glioma patients.
- Treatment with prostaglandin E2 (PGE2) and agents that increase intracellular cyclic adenosine monophosphate (cAMP) levels.
- Assessed cytolytic activity against autologous/allogeneic tumor cells and Daudi cell line after interleukin-2 (IL-2) expansion.
Main Results:
- PGE2 and cAMP-elevating agents significantly suppressed IL-2-dependent LAK cell generation from PBL and TILs.
- Higher IL-2 concentrations or cyclic guanosine monophosphate did not overcome the inhibitory effects.
- PGE2 inhibited LAK cell generation early in the process and also directly in cytotoxicity assays.
Conclusions:
- PGE2 and elevated cAMP levels are potent inhibitors of anti-tumor immune responses in glioblastoma.
- Glioblastoma-derived PGE2 may regulate the generation of immune responses and the efficacy of immunotherapy in vivo.
- Targeting PGE2 or cAMP pathways could be a strategy to enhance immunotherapy for glioblastoma.