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Published on: September 1, 2018
Microglia phagocytose alloreactive CTL-damaged 9L gliosarcoma cells
Nisha V Kulprathipanja1, Carol A Kruse
1Department of Immunology, University of Colorado Health Sciences Center, 4200 E. 9th Avenue, B216, Denver, CO 80262, USA.
Abstract:
Intracranial adoptive transfers of alloreactive cytotoxic T lymphocytes (aCTL) for brain tumor treatment were safe and showed promise in preclinical and early clinical trials. To better understand the endogenous immune responses that may ensue following cellular therapy with aCTL, we examined the ability of microglia to phagocytose aCTL-damaged and undamaged rat 9L gliosarcoma cells in vitro and in vivo. In vitro, 5.5+/-0.9% of microglial cells isolated from adult tumor-bearing rat brains phagocytosed aCTL-damaged 9L cells, whereas microglia did not bind to or ingest undamaged 9L cells. Addition of supernates from either 9L cell cultures or from aCTL+9L co-incubate cell cultures to microglia did not significantly alter their ability to bind to or phagocytose damaged glioma cells even though the latter contained T helper 1 and 2 cytokines. At 3 days following intracranial 9L cell infusion, 17.5+/-0.1% of the microglia phagocytosed CFSE-labeled aCTL-damaged 9L tumor cells within the adult rat brain, confirming the in vitro data. The results suggest that microglia within the tumor microenvironment of the adult rat glioma model selectively remove damaged, but not undamaged, glioma cells.
Insights
Microglia in rat brains selectively engulf damaged glioma cells after T cell therapy. This immune response targets only tumor cells harmed by alloreactive cytotoxic T lymphocytes (aCTL), not healthy ones.
Area of Science:
- Immunology
- Neuro-oncology
- Cellular Biology
Background:
- Intracranial adoptive T cell therapy shows promise for brain tumors.
- Understanding endogenous immune responses to cellular therapy is crucial.
- Microglia play a key role in the brain's immune surveillance.
Purpose of the Study:
- To investigate microglia's phagocytic activity towards alloreactive cytotoxic T lymphocyte (aCTL)-damaged and undamaged 9L gliosarcoma cells.
- To assess microglia's role in the immune response following aCTL therapy in a rat glioma model.
Main Methods:
- In vitro analysis of microglia phagocytosis of 9L gliosarcoma cells (damaged vs. undamaged) using cells from tumor-bearing rat brains.
- In vivo assessment of microglia phagocytosis of CFSE-labeled aCTL-damaged 9L tumor cells within the rat brain post-intracranial infusion.
- Analysis of cytokine presence in cell culture supernates.
Main Results:
- Microglia isolated from tumor-bearing rat brains phagocytosed aCTL-damaged 9L cells in vitro (5.5+/-0.9%), but not undamaged cells.
- Supernates from 9L or aCTL+9L co-cultures did not significantly alter microglia's phagocytic ability towards damaged glioma cells.
- In vivo, 17.5+/-0.1% of microglia phagocytosed aCTL-damaged 9L tumor cells within the brain 3 days after infusion.
Conclusions:
- Microglia in the tumor microenvironment selectively phagocytose damaged glioma cells.
- This selective phagocytosis occurs for both aCTL-damaged and undamaged glioma cells.
- Microglia contribute to the clearance of damaged tumor cells following T cell-based immunotherapy.
