Glioblastoma cells acquire myeloid-affiliated transcriptional programs via epigenetic immunoediting to elicit immune evasion [BiSulfite-seq]

Glioblastoma multiforme (GBM) is an aggressive brain tumour. Current immunotherapy approaches have been unsuccessful, highlighting the need to determine underlying mechanisms of immune evasion. Here, we developed syngeneic immunocompetent mouse models of GBM to explore this. GBM stem cells (GSCs) were serially transplanted through immunocompetent hosts, which uncovered an acquired capability to escape immune clearance through an enhanced immunosuppressive tumour microenvironment. Mechanistically, this was not elicited via genetic selection of tumour subclones, but through an epigenetic immunoediting process wherein stable transcriptional and epigenetic changes in GSCs are enforced following immune attack. These include activation of interferon signalling modules, myeloid-affiliated transcription factors and chemokines, which leads to increased recruitment of tumour-associated macrophages. Furthermore, we identify similar epigenetic and transcriptional signatures in human mesenchymal subtype GSCs. We conclude that epigenetic immunoediting may drive an acquired immune evasion program in the most aggressive mesenchymal GBM subtype by reshaping the tumour immune microenvironment.