Epigenetic Underpinnings of Inflammation: A Key to Unlock the Tumor Microenvironment in Glioblastoma

Abstract

Glioblastoma (GBM) is the most common malignant brain tumor in adults, and immunotherapies and genetic therapies for GBM have evolved dramatically over the past decade, but GBM therapy is still facing a dilemma due to the high recurrence rate. The inflammatory microenvironment is a general signature of tumors that accelerates epigenetic changes in GBM and helps tumors avoid immunological surveillance. GBM tumor cells and glioma-associated microglia/macrophages are the primary contributors to the inflammatory condition, meanwhile the modification of epigenetic events including DNA methylation, non-coding RNAs, and histone methylation and deacetylases involved in this pathological process of GBM, finally result in exacerbating the proliferation, invasion, and migration of GBM. On the other hand, histone deacetylase inhibitors, DNA methyltransferases inhibitors, and RNA interference could reverse the inflammatory landscapes and inhibit GBM growth and invasion. Here, we systematically review the inflammatory-associated epigenetic changes and regulations in the microenvironment of GBM, aiming to provide a comprehensive epigenetic profile underlying the recognition of inflammation in GBM.

Keywords: GBM tumor cells; epigenetic regulation; glioblastoma; glioma-associated microglia/macrophages; inflammation; microenvironment.

Figure 1

Inflammation-related changes in GBM tumor cells. GBM tumor cells produce abundant IL-1 and IL-6 through activating various pathways including STAT3, RAS, NFκB, NLRP3, and HIF-1α pathways, thus creating a chronic inflammatory environment, which benefits GBM growth.

Figure 2

Chronic inflammation induced M2 GAMs. Under chronic inflammation, most GAMs are polarized to the M2 type by STAT3 and NFκB activation, which produces high levels of VEGF and immunosuppressive factors including IL-6, IL-8, IL-10, Arg1, TGF-β, and PD-L1, eventually inducing more M2 polarizations and accelerating GBM growth and evasion in turn.

Figure 3

Cellular communication in GBM. Under chronic inflammation, cytokines released by cells including somatic cells and other immune cells can recruit GAM infiltration after the survey and chemotherapy and immunotherapy treatments in GBM. Additionally, GBM tumor cells induce GAM polarization resulting in disrupting the balance of M1 and M2 GAMs. Meanwhile, GBM tumor cells communication with astrocytes and other somatic cells could impair T cell function and release plenty of cytokines including IL-6, IL-4, IL-10, IL-8, IL-1, TGF-β, Arg-1, and VEGF. All these changes aggravate GBM tumor growth.