Abstract
Glioblastoma multiforme, the most aggressive primary brain tumor, is maintained by a subpopulation of glioma cells with self-renewal properties that are able to recapitulate the entire tumor even after surgical resection or chemo-radiotherapy. This typifies the vast heterogeneity of this tumor with the two extremes represented on one end by the glioma stemlike cells (GSC) and on the other by the glioma differentiated cells (GDC). Interestingly, GSC are more sensitive to immune effector cells than the GDC counterpart. However, how GSC impact on the killing on the GDC and vice versa is not clear. Using a newly developed cytotoxicity assay allowing to simultaneously monitor cytotoxic lymphocytes-mediated killing of GSC and GDC, we found that although GSC were always better killed and that their presence enhanced the killing of GDC. In contrast, an excess of GDC had a mild protective effect on the killing of GSC, depending on the CTL type. Overall, our results suggest that during combination therapy, immunotherapy would be the most effective after prior treatment with conventional therapies.
Highlights
Glioblastoma multiforme (GBM), the highly heterogeneous and the most frequent and lethal primary brain tumor [1], is refractory to conventional therapy combining surgical resection, radiotherapy and chemotherapy [2]
In order to test which of glioma stemlike cells (GSC) and the GDC are more sensitive to cytotoxic immune cells we first used U251 human glioma differentiated cells (GDC) and their neurosphere GSC counterpart to investigate their relative susceptibility to natural killer cells
Using U251 human and GL261 mouse glioma models and YT-Indy natural killer cells or PMEL and OT-1 CTL, two well characterized mouse killer lymphocyte models, we confirmed that both glioma differentiated cells (GDC) and neurosphere (NS) glioma stemlike cells (GSC) are effectively killed by natural killer cells and cytotoxic T lymphocytes
Summary
Glioblastoma multiforme (GBM), the highly heterogeneous and the most frequent and lethal primary brain tumor [1], is refractory to conventional therapy combining surgical resection, radiotherapy and chemotherapy [2]. Patients diagnosed with this difficult to cure disease only have 14.6 months of median survival [1, 3, 4]. The different types of tumor cells are involved in interaction with neighboring stromal and cancer cells, or with the immune infiltrate constituting the microanatomy of the tumor. GSC and their glioma differentiated cell (GDC) counterpart would be the two extremes of the spectrum of variability comprising the PLOS ONE | DOI:10.1371/journal.pone.0153433 April 13, 2016
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