Glioblastomas are highly infiltrated by diverse immune cells, including microglia, macrophages, and myeloid-derived suppressor cells (MDSCs). Understanding the mechanisms by which glioblastoma-associated myeloid cells (GAMs) undergo metamorphosis into tumor-supportive cells, characterizing the heterogeneity of immune cell phenotypes within glioblastoma subtypes, and discovering new targets can help the design of new efficient immunotherapies. In this study, we performed a comprehensive battery of immune phenotyping, whole-genome microarray analysis, and microRNA expression profiling of GAMs with matched blood monocytes, healthy donor monocytes, normal brain microglia, nonpolarized M0 macrophages, and polarized M1, M2a, M2c macrophages. Glioblastoma patients had an elevated number of monocytes relative to healthy donors. Among CD11b+ cells, microglia and MDSCs constituted a higher percentage of GAMs than did macrophages. GAM profiling using flow cytometry studies revealed a continuum between the M1- and M2-like phenotype. Contrary to current dogma, GAMs exhibited distinct immunological functions, with the former aligned close to nonpolarized M0 macrophages.

Glioblastoma remains the most common and devastating primary brain tumor despite maximal therapy with surgery, chemotherapy, and radiation. The glioma stem cell (GSC) subpopulation has been identified in glioblastoma and likely plays a key role in resistance of these tumors to conventional therapies as well as recurrent disease. GSCs are capable of self-renewal and differentiation; glioblastoma-derived GSCs are capable of de novo tumor formation when implanted in xenograft models. Further, GSCs possess unique surface markers, modulate characteristic signaling pathways to promote tumorigenesis, and play key roles in glioma vascular formation. These features, in addition to microenvironmental factors, present possible targets for specifically directing therapy against the GSC population within glioblastoma. In this review, the authors summarize the current knowledge of GSC biology and function and the role of GSCs in new vascular formation within glioblastoma and discuss potential therapeutic approaches to target GSCs.

Stem cells including cancer stem cells (CSCs) require niches to maintain stemness, yet it is unclear how CSCs maintain stemness in the suboptimal environment outside their niches during invasion. Postnatal codeletion of Pten and Trp53 in mouse neural stem cells (NSCs) leads to their expansion in the subventricular zone (SVZ) niches but fails to maintain the stemness outside the SVZs. We discovered that QKI is a major regulator of NSC stemness. Qki deletion against Pten−/−Trp53−/− backdrop helps NSCs maintain their stemness outside the SVZs in Nestin-CreERT2 QkiL/LPtenL/LTrp53L/L mice, which develop glioblastoma with a penetrance of 92% and a median survival of 105 days. Mechanistically, Qki deletion decreases endolysosome-mediated degradation and enriches receptors essential for maintaining self-renewal on the cytoplasmic membrane to cope with low ligand levels outside the niches. Thus, downregulating endolysosome level by QKI loss helps glioma stem cells (GSCs) maintain their stemness in suboptimal environments outside the niches.