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Damage to multicellular human H-2 glioma spheroids incubated with LAK cells: an ultrastructural study
J Jääskeläinen1, E Lehtonen, P Heikkilä
1Department of Neurosurgery, Helsinki University Central Hospital, Finland.
Abstract:
Local brain tumor therapy using lymphokine-activated killer (LAK) cells and recombinant interleukin-2 (rIL-2) has not proved to be effective in preliminary clinical trials. One obstacle to effective use of this therapy is ignorance about the events that follow contact of the LAK cells with glioma tissue. We used multicellular spheroids grown from human glioma cell lines as targets to study, in vitro, the effect of LAK cells against three-dimensional glioma tissue. Here we describe the ultrastructural changes in spheroids of H-2 glioma cells incubated in pellets of LAK cells for up to 24 hours. In H-2 spheroids, cellular damage was not restricted to the effector cell-target cell (effector-target) contact; it extended farther, at least partly because of nonspecific changes in the spheroid micromilieu. Formation of cytoplasmic blebs, a characteristic effect of T cells, natural killer cells, and LAK cells on single target cells, also occurs in H-2 spheroids, and it is not limited to the effector-target contact area either. These findings suggest that LAK cells release membrane-damaging agents that remain active outside the effector-target area, in the micromilieu of H-2 spheroid tissue.
Insights
Local brain tumor therapy using lymphokine-activated killer (LAK) cells and recombinant interleukin-2 (rIL-2) is ineffective. LAK cells damage glioma tissue beyond direct contact, suggesting release of active agents into the spheroid microenvironment.
Area of Science:
- Neuro-oncology
- Immunotherapy
- Cellular biology
Background:
- Local brain tumor therapy with lymphokine-activated killer (LAK) cells and recombinant interleukin-2 (rIL-2) has shown limited efficacy in clinical trials.
- Understanding the interaction between LAK cells and glioma tissue is crucial for improving treatment strategies.
Purpose of the Study:
- To investigate the ultrastructural changes in three-dimensional human glioma spheroids upon incubation with LAK cells.
- To elucidate the mechanism of LAK cell-mediated damage in a complex tumor microenvironment.
Main Methods:
- Human H-2 glioma cell lines were cultured as multicellular spheroids.
- Spheroids were incubated with pellets of LAK cells for up to 24 hours.
- Ultrastructural analysis was performed using electron microscopy to observe cellular changes.
Main Results:
- Cellular damage within the H-2 glioma spheroids extended beyond the direct effector-target cell contact zones.
- Nonspecific changes in the spheroid microenvironment contributed to the widespread cellular damage.
- Formation of cytoplasmic blebs, a hallmark of LAK cell activity, was observed and was not confined to the contact area.
Conclusions:
- LAK cells induce damage in three-dimensional glioma tissue that is not limited to direct cell-cell interactions.
- These findings suggest that LAK cells release membrane-damaging agents that can affect tumor cells in the surrounding microenvironment.
- This suggests a potential mechanism for the limited effectiveness of LAK cell therapy in brain tumors.