title: Decitabine Treatment of Glioma-Initiating Cells Enhances Immune Recognition and Killing.
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.
authors: Centre of Oncology, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.
authors: Cristina
authors: C
authors: Riccadonna
authors: Centre of Oncology, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.
authors: Céline
authors: C
authors: Yacoub Maroun
authors: Centre of Oncology, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.
authors: Romain
authors: R
authors: Vuillefroy de Silly
authors: Centre of Oncology, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.
authors: Margaux
authors: M
authors: Boehler
authors: Centre of Oncology, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.
authors: Marta
authors: M
authors: Calvo Tardón
authors: Astex Pharmaceuticals, Cambridge Science Park, Cambridge, United Kingdom.
authors: Simone
authors: S
authors: Jueliger
authors: Astex Pharmaceuticals, Pleasanton, CA, United States of America.
authors: Pietro
authors: P
authors: Taverna
authors: Centre of Oncology, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.
authors: Leticia
authors: L
authors: Barba
authors: Centre of Oncology, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.
authors: Eliana
authors: E
authors: Marinari
authors: Unit of Molecular Neuro-Oncology, Fondazione I.R.C.C.S. Istituto Neurologico C. Besta, Milan, Italy.
authors: Serena
authors: S
authors: Pellegatta
authors: Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.
authors: Esen Yonca
authors: EY
authors: Bassoy
authors: Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.
authors: Denis
authors: D
authors: Martinvalet
authors: Centre of Oncology, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.
authors: Pierre-Yves
authors: PY
authors: Dietrich
authors: Centre of Oncology, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.
authors: Paul R
authors: PR
authors: Walker
mesh_terms: D000818:Animals; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000077209:Decitabine; D053222:Fas Ligand Protein / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005805:Genes, MHC Class I / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays; D019014:fas Receptor / Q000235:genetics* / Q000378:metabolism
chemical_list: D053222:Fas Ligand Protein; C491899:Fas protein, mouse; D019014:fas Receptor; D018799:Intercellular Adhesion Molecule-1; D000077209:Decitabine; D001374:Azacitidine