TNF‐α‐ and TRAIL‐resistant glioma cells undergo autophagy‐dependent cell death induced by activated microglia

Abstract

The role of microglia, the brain resident macrophages, in glioma biology is still ill-defined. Despite their cytotoxic potential, these cells that significantly infiltrate the tumor mass seem to support tumor growth rather than tumor eradication. A proper activation of microglia anti-tumor activities within the tumor may provide a valuable additional arm of defense to immunotherapies against brain tumors. We herewith report a detailed characterization of (lipopolysaccharide and interferon-gamma)-induced anti-tumor activities of mouse primary microglia towards two TNF-alpha and TRAIL resistant glioma cell lines, in cell monolayer or spheroid cultures and in collagen-embedded tumor explants. Irrespective of the mouse strain, stimulated microglia secreted proteic factors that decreased proliferation and migration of these glioma cells and efficiently killed them. Death occurred specifically in glioma cells as demonstrated by the lack of toxicity of microglia supernatant towards primary cultures of astrocytes or neurons. Cell death was characterized by the early accumulation of acidic vesicles, phosphatidylserine exposure, appearance of double-membrane cytoplasmic vesicles, extensive zeiosis and a very late loss of DNA in cells that had lost membrane integrity. Inhibition of autophagosome formation efficiently protected glioma cells from death whereas caspase inhibition could only prevent DNA loss but not cytotoxicity. Death however, resulted from a blockade by microglia supernatant of the basal autophagic flux present in the glioma cells. These observations demonstrate that glioma cells resistant to apoptotic death ligands could be successfully and specifically killed through autophagy-dependent death induced by appropriately activated microglia.

Paclitaxel Treatment and Proprotein Convertase 1/3 (PC1/3) Knockdown in Macrophages is a Promising Antiglioma Strategy as Revealed by Proteomics and Cytotoxicity Studies

“…Of note, we showed that the effect observed is higher than the direct effect of Paclitaxel alone. In 3D co-culture experiments, untreated or treated with low doses of Paclitaxel, macrophages supported the growth and invasion of glioma cells (Figure 7Ab), as expected from previous observations with murine microglia and human tumorassociated microglia/macrophages 68,69 . We showed that these supportive activities were suppressed by a pre-treatment of macrophages with Paclitaxel, which triggered an efficient antitumor response.…”

Enteroglial cells act as antigen-presenting cells in chagasic megacolon

“…The capacity of EGCs for phagocytosis and cytokine-inducible HLA-DR complex class II expression, which is fully functional for antigen-specific T-cell activation, has been confirmed in tissue culture experiments [36]. The EGCs are morphologically and molecularly similar to CNS astrocytes [37,38]; thus, they presumably share some functions with these cells, such as structural, metabolic, trophic, and protective support of neurons [39].…”

Genetically engineered Newcastle disease virus expressing interleukin-2 and TNF-related apoptosis-inducing ligand for cancer therapy

“…[29][30][31] Nevertheless, some studies have found that tumors easily build resistance to TRAIL-based therapies. 32,33 Tumor cell resistance to TRAIL seemed to occur through the modulation of various molecular targets, including differential expression of death receptors, overexpression of anti-apoptotic molecules, mutations in apoptotic genes, defected in caspase signaling, and caspase inhibition in resistant cells. 34,35 In this study, we expressed TRAIL delivered by rNDV to improve the effect of cancer therapy.…”