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

Abstract

Summary 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.

Harnessing the Activation of RIG-I Like Receptors to Inhibit Glioblastoma Tumorigenesis

“…The high heterogeneity of GB appears to reflect distinct GB immune subsets based on the molecular signature (Luoto et al, 2018 ). A number of evidence has underlined that specific genetic alterations or epigenetic signatures can be associated with a better response to immunotherapy, and could help for selecting subgroups of GB patients (Parsa et al, 2007 ; Rutledge et al, 2013 ; Berghoff et al, 2017 ; Gangoso et al, 2021 ).…”

“…Unfortunately, the disease remains incurable and often returns as recurrent GB (Lieberman, 2017 ). Limited progress in the development of more effective therapeutic approaches for GB is mostly due to its heterogeneous genetic, molecular landscape, and cell plasticity (Brennan et al, 2013 ; Meyer et al, 2015 ; Gangoso et al, 2021 ).…”

From blood to brain: blood cell-based biomimetic drug delivery systems

“…Abnormal activation of platelets may increase bleeding and thrombosis risks. Platelets are regulators of neuroinflammation and play important roles in the integrity of BBB (Brailoiu et al., 2018 ; Gao et al., 2020 ). Currently, for brain drug delivery, platelet-based vehicles are being used solely for ischemic stroke therapy as they may have limited BBB penetration ability under other brain diseased status.…”

Molecular Mechanisms of Drug Resistance in Glioblastoma

“…GBM develops from astrocytes and spreads to nearby brain tissue [6]. Some restructuring of the classification of tumors of the Central Nervous System was made by the World Health Organization in 2016 using molecular and histological parameters [7].…”

“…GBM was divided in: (1) isocitrate dehydrogenase (IDH)-wild type (about 90% of cases), which consists of giant cell glioblastoma, gliosarcoma, epithelioid glioblastoma; (2) IDH-mutant glioblastoma (about 10% of cases); (3) glioblastoma, NOS, for which full IDH evaluation is impossible. GBM is one of the best characterized genomic cancers, several types are distinguished according to their transcriptional profile (proneural, neural, classical, and mesenchymal or edge, edge-like, core, core-like), genetics (mutations in IDH gene), and epigenetics (CpG island methylation phenotype (CIMP), O 6 methylguanine-DNA methyltransferase (MGMT) promoter methylation) [8][9][10][11][12].…”