Abstract
Malignant gliomas are aggressive brain tumours with very poor prognosis. The majority of glioma cells are differentiated (glioma-differentiated cells: GDCs), whereas the smaller population (glioma-initiating cells, GICs) is undifferentiated and resistant to conventional therapies. Therefore, to better target this pool of heterogeneous cells, a combination of diverse therapeutic approaches is envisaged. Here we investigated whether the immunosensitising properties of the hypomethylating agent decitabine can be extended to GICs. Using the murine GL261 cell line, we demonstrate that decitabine augments the expression of the death receptor FAS both on GDCs and GICs. Interestingly, it had a higher impact on GICs and correlated with an enhanced sensitivity to FASL-mediated cell death. Moreover, the expression of other critical molecules involved in cognate recognition by cytotoxic T lymphocytes, MHCI and ICAM-1, was upregulated by decitabine treatment. Consequently, T-cell mediated killing of both GDCs and GICs was enhanced, as was T cell proliferation after reactivation. Overall, although GICs are described to resist classical therapies, our study shows that hypomethylating agents have the potential to enhance glioma cell recognition and subsequent destruction by immune cells, regardless of their differentiation status. These results support the development of combinatorial treatment modalities including epigenetic modulation together with immunotherapy in order to treat heterogenous malignancies such as glioblastoma.
Highlights
Malignant gliomas are highly invasive and heterogeneous brain tumours
In order to characterise the GL261 GDC and GIC cell lines, we investigated their neural stemcell marker expression in vitro and their tumourigenic potential
To further confirm that GDCs and GICs had a diverse differentiation status, we tested the expression of the glial fibrillary acidic protein (Gfap), an astrocyte differentiation marker reported to be absent in GICs [33, 35, 36]
Summary
Malignant gliomas are highly invasive and heterogeneous brain tumours. Among the different types of gliomas, glioblastomas (GBMs) represent the most deadly primary brain tumours [1]. In a murine mammary carcinoma model, this was directly linked to enhanced expression of the CTA P1A and lung metastases were significantly reduced after combined DAC treatment and adoptive transfer of specific CTLs [26] In accordance with these findings, combinations of epigenetic drugs and immunotherapies such as immune checkpoint inhibitors have begun to be investigated in clinic trials for cancer treatment [27]. DAC is a promising anti-neoplastic agent to be potentially used in combination with T cell-based immunotherapy in glioma These studies only used human GBM lines grown under conventional culture conditions that will represent GDCs rather than GICs (which require serum free culture in presence of neural stem cell growth factors). DAC sensitised glioma cells to CTL-mediated killing, regardless of their differentiation status
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
