Decitabine treatment of glioma-initiating cells enhances immune recognition and killing

Cristina Riccadonna, Céline Yacoub Maroun, Romain Vuillefroy De Silly, Margaux Boehler, Marta Calvo Tardón, Simone Jueliger, Pietro Taverna, Leticia Barba, Eliana Marinari, Serena Pellegatta, Esen Yonca Bassoy, Denis Martinvalet, Pierre Yves Dietrich, Paul R. Walker

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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.

Original languageEnglish
Article numbere0162105
JournalPLoS One
Volume11
Issue number8
DOIs
Publication statusPublished - Aug 1 2016

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ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Riccadonna, C., Yacoub Maroun, C., Vuillefroy De Silly, R., Boehler, M., Calvo Tardón, M., Jueliger, S., Taverna, P., Barba, L., Marinari, E., Pellegatta, S., Bassoy, E. Y., Martinvalet, D., Dietrich, P. Y., & Walker, P. R. (2016). Decitabine treatment of glioma-initiating cells enhances immune recognition and killing. PLoS One, 11(8), [e0162105]. https://doi.org/10.1371/journal.pone.0162105