Glioblastomas acquire myeloid-affiliated transcriptional programs via epigenetic immunoediting to elicit immune evasion

Glioblastoma multiforme (GBM) is an aggressive brain tumor for which current immunotherapy approaches have been unsuccessful. Here, we explore the mechanisms underlying immune evasion in GBM. By serially transplanting GBM stem cells (GSCs) into immunocompetent hosts, we uncover an acquired capability of GSCs to escape immune clearance by establishing an enhanced immunosuppressive tumor microenvironment. Mechanistically, this is not elicited via genetic selection of tumor subclones, but through an epigenetic immunoediting process wherein stable transcriptional and epigenetic changes in GSCs are enforced following immune attack. These changes launch a myeloid-affiliated transcriptional program, which leads to increased recruitment of tumor-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 tumor immune microenvironment. [Display omitted] •Disease-relevant TME is recapitulated in immunocompetent GBM mouse models•Stable reconfiguration of the transcriptome occurs in GSCs following immune attack•Immune evasive GSCs deploy “myeloid mimicry” to establish a myeloid-enriched TME•Acquired transcriptional changes consistent with a process of epigenetic immunoediting Glioblastoma stem cells deploy a myeloid mimicry program through epigenetic immunoediting, rather than subclonal selection, to drive a myeloid-enriched tumor microenvironment, thereby enabling immune evasion and tumor progression.