Effects of glioblastoma-derived extracellular vesicles on the functions of immune cells

Abstract

Glioblastoma is the most aggressive variant of glioma, the tumor of glial origin which accounts for 80% of brain tumors. Glioblastoma is characterized by astoundingly poor prognosis for patients; a combination of surgery, chemo- and radiotherapy used for clinical treatment of glioblastoma almost inevitably results in rapid relapse and development of more aggressive and therapy resistant tumor. Recently, it was demonstrated that extracellular vesicles produced by glioblastoma (GBM-EVs) during apoptotic cell death can bind to surrounding cells and change their phenotype to more aggressive. GBM-EVs participate also in establishment of immune suppressive microenvironment that protects glioblastoma from antigen-specific recognition and killing by T cells. In this review, we collected present data concerning characterization of GBM-EVs and study of their effects on different populations of the immune cells (T cells, macrophages, dendritic cells, myeloid-derived suppressor cells). We aimed at critical analysis of experimental evidence in order to conclude whether glioblastoma-derived extracellular vesicles are a major factor in immune evasion of this deadly tumor. We summarized data concerning potential use of GBM-EVs for non-invasive diagnostics of glioblastoma. Finally, the applicability of approaches aimed at blocking of GBM-EVs production or their fusion with target cells for treatment of glioblastoma was analyzed.

Keywords: T cell response; extracellular vesicles; glioblastoma multiforme; immune response; immune suppression; signaling pathways.

FIGURE 1

Scheme shows major protein membrane components and lipids of GBM-EVs and classes of cargo molecules (non-coding RNAs, mRNAs and cytosolic proteins, adopted with modifications from Benecke et al., 2021; Naryzhny et al. 2020).

FIGURE 2

Schematic representation of GBM-EVs effects on the myeloid immune cells mediated by transfer of the cargo molecules (mostly RNAs). GBM-EVs (on the top) fuse with or get phagocytosed by macrophages, myeloid-derived suppressor cells (MDSC) and dendritic cells (DC) causing changes in phenotype of recipient cells. Cargo molecules participating in reprogramming and resulting phenotypic responses (Cheryl et al., 2013; Mooij et al., 2020; Liang et al., 2019; Jung et al., 2022) are shown as red (negative effect) or green (positive effect) arrows with supporting text. Subsequent influence of changes in myeloid cells negatively affect anti-tumor immunity by suppressing functions of CD4⁺ effector cells and CD8⁺ cytotoxic lymphocytes (on the bottom).

FIGURE 3

Schematic representation of GBM-EVs effects on the immune cells mediated by the surface molecules. GBM-EVs (in the middle) carry molecules participating in ligand-receptor interactions with molecules on the surface of immune cells (adopted with modifications from Scholl et al., 2020; Ricklefs et al., 2016; Jung et al., 2022; Dusoswa et al., 2019). The changes in immune cells are indicated with arrows with supporting text. Chart in the upper right corner explains the symbols used to show different membrane proteins from GBM-EVs.