CD73-positive extracellular vesicles promote glioblastoma immunosuppression by inhibiting T-cell clonal expansion

Abstract

Extracellular vesicles are involved in the occurrence, progression and metastasis of glioblastoma (GBM). GBM can secrete a variety of tumour-derived extracellular vesicles (TDEVs) with high immunosuppressive activity that remotely suppress the systemic immune system, and therapy targeting TDEVs has potential efficacy. In this study, we detected a higher concentration of CD73+ TDEVs enriched in exosomes in central and peripheral body fluids of GBM patients than in those of patients with other brain tumours (low-grade glioma or brain metastases from melanoma or non-small-cell lung cancer). High CD73 expression was detected on the surface of T cells, and this CD73 was derived from TDEVs secreted by GBM cells. In vitro, we observed that CD73+ TDEVs released by GBM cell lines could be taken up by T cells. Moreover, excess adenosine was produced by AMP degradation around T cells and by adenosine receptor 2A (A2AR)-dependent inhibition of aerobic glycolysis and energy-related metabolic substrate production, thereby inhibiting the cell cycle entry and clonal proliferation of T cells. In vivo, defects in exosomal synthesis and CD73 expression significantly inhibited tumour growth in GBM tumour-bearing mice and restored the clonal proliferation of T cells in the central and peripheral regions. These data indicate that CD73+ TDEVs can be used as a potential target for GBM immunotherapy.

Tumor-derived small extracellular vesicles: potential roles and mechanism in glioma

“…The CD73 + TDEVs released by GBM cells could be taken up by T cells and inhibit cell cycle entry and clonal proliferation of T cells. Defects in exosome synthesis and CD73 expression remarkably repressed tumor growth in GBM-bearing mice and restored clonal proliferation of T cells in peripheral and central regions [ 75 ].…”

“…Defects in exosome synthesis and CD73 expression remarkably repressed tumor growth in GBM-bearing mice and restored clonal proliferation of T cells in peripheral and central regions [ 75 ].…”

Dynamic Intercell Communication between Glioblastoma and Microenvironment through Extracellular Vesicles

“…They can change the immune microenvironment, impacting chemo- and immune checkpoint blockers therapy. As such, cargos LGALS9 [ 38 ] and CD73 were identified [ 39 ]. In the central nervous system microglial cells EVs were determined to carry pro-inflammatory cytokine IL-1β and therefore to propagate inflammation [ 40 ].…”

Tumour Derived Extracellular Vesicles: Challenging Target to Blunt Tumour Immune Evasion

“…MDSC, Treg or DC expressing CD73 generate adenosine in tumours, which triggers the anti-inflammatory response via T-cells, macrophages, and natural killer cells (NK) [ 138 , 139 ]. Several studies have reported that the expression of CD73 in TEV also contributes to immunosuppression in different cancers [ 140 , 141 ]. TEV transfer CD73 to T-cells and inhibit their cell cycle entry and clonal proliferation by increasing adenosine [ 140 ].…”

“…Several studies have reported that the expression of CD73 in TEV also contributes to immunosuppression in different cancers [ 140 , 141 ]. TEV transfer CD73 to T-cells and inhibit their cell cycle entry and clonal proliferation by increasing adenosine [ 140 ]. Consistently, inhibition of TEV production or CD73 expression significantly inhibit tumour growth by restoring T-cell clonal proliferation [ 140 ].…”