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.

The Brain Microenvironment Induces DNMT1 Suppression and Indolence of Metastatic Cancer Cells

“…In cases where metastatic cells transition to active growth, their apparent dependence on αB-crystallin decreases. Thus, in addition to the possibility of blood-brain barrier-permeable decitabine for the treatment of growing brain metastasis ( Chabot et al., 1983 ; Riccadonna et al., 2016 ; Tawbi et al., 2013 ), targeting αB-crystallin and other pro-survival factors expressed in dormant cells may represent an attractive strategy for eliminating indolent single cells and micro-clusters. Furthermore, we can also hypothesize from our results that only the cells that undergo reprograming for cell survival and also circumvent anti-proliferative effects might progress to macrometastasis.…”

Prognostic value of indoleamine 2,3 dioxygenase in patients with higher‐risk myelodysplastic syndromes treated with azacytidine

“…This is consistent with several publications in which TP53 mutations conferred a poor prognosis but were not predictive of the response to therapy, 6,38,39 while IPSS-R, Consequently, the T cell-mediated elimination of tumour cells is enhanced due to T cell recruitment and proliferation after reactivation. 40,41 IDO-1 expression correlated inversely with the CD8/CD3 ratio in our bone marrow samples; therefore, it might well be that IDO-1 counteracts the immune cell activation of AZA and thereby promotes resistance to therapy. The level of CD8 + T cells clearly increased after/under AZA treatment and remained constantly high.…”

“…HMAs can potentiate antitumour immunity by inducing the expression of critical molecules involved in cognate recognition by cytotoxic T cells, such as MHC I and ICAM‐1. Consequently, the T cell‐mediated elimination of tumour cells is enhanced due to T cell recruitment and proliferation after reactivation 40,41 . IDO‐1 expression correlated inversely with the CD8/CD3 ratio in our bone marrow samples; therefore, it might well be that IDO‐1 counteracts the immune cell activation of AZA and thereby promotes resistance to therapy.…”

Epigenetic downregulation of STAT6 increases HIF-1α expression via mTOR/S6K/S6, leading to enhanced hypoxic viability of glioma cells

“…Because HIF-1α is critical for GSC maintenance [37, 43], STAT6 downregulation may favor HIF-1α accumulation in GSCs under hypoxic conditions, thereby contributing to GSC maintenance and GBM progression. Furthermore, 5-Aza is capable of targeting GSCs [40]; thus, restoration of STAT6 may be another mechanism underlying the actions of 5-Aza against GSCs.…”