Decitabine Treatment of Glioma-Initiating Cells Enhances Immune Recognition and Killing.

Autor:	Riccadonna C; Centre of Oncology, Geneva University Hospitals and University of Geneva, Geneva, Switzerland., Yacoub Maroun C; Centre of Oncology, Geneva University Hospitals and University of Geneva, Geneva, Switzerland., Vuillefroy de Silly R; Centre of Oncology, Geneva University Hospitals and University of Geneva, Geneva, Switzerland., Boehler M; Centre of Oncology, Geneva University Hospitals and University of Geneva, Geneva, Switzerland., Calvo Tardón M; Centre of Oncology, Geneva University Hospitals and University of Geneva, Geneva, Switzerland., Jueliger S; Astex Pharmaceuticals, Cambridge Science Park, Cambridge, United Kingdom., Taverna P; Astex Pharmaceuticals, Pleasanton, CA, United States of America., Barba L; Centre of Oncology, Geneva University Hospitals and University of Geneva, Geneva, Switzerland., Marinari E; Centre of Oncology, Geneva University Hospitals and University of Geneva, Geneva, Switzerland., Pellegatta S; Unit of Molecular Neuro-Oncology, Fondazione I.R.C.C.S. Istituto Neurologico C. Besta, Milan, Italy., Bassoy EY; Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland., Martinvalet D; Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland., Dietrich PY; Centre of Oncology, Geneva University Hospitals and University of Geneva, Geneva, Switzerland., Walker PR; Centre of Oncology, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.
Jazyk:	angličtina
Zdroj:	PloS one [PLoS One] 2016 Aug 31; Vol. 11 (8), pp. e0162105. Date of Electronic Publication: 2016 Aug 31 (Print Publication: 2016).
DOI:	10.1371/journal.pone.0162105
Abstrakt:	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. Competing Interests: SJ and PT are employees of Astex Pharmaceuticals. The authors have declared that no competing interests exist.
Databáze:	MEDLINE
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