Cancer Stem Cells and Immunosuppressive Microenvironment in Glioma

Abstract

Glioma is one of the most common malignant tumors of the central nervous system and is characterized by extensive infiltrative growth, neovascularization, and resistance to various combined therapies. In addition to heterogenous populations of tumor cells, the glioma stem cells (GSCs) and other nontumor cells present in the glioma microenvironment serve as critical regulators of tumor progression and recurrence. In this review, we discuss the role of several resident or peripheral factors with distinct tumor-promoting features and their dynamic interactions in the development of glioma. Localized antitumor factors could be silenced or even converted to suppressive phenotypes, due to stemness-related cell reprogramming and immunosuppressive mediators in glioma-derived microenvironment. Furthermore, we summarize the latest knowledge on GSCs and key microenvironment components, and discuss the emerging immunotherapeutic strategies to cure this disease.

Keywords: cancer stem cell; glioma; immunosuppression; immunotherapy; tumor microenvironment.

Figure 1

Therapeutic approaches targeting GSCs are critical in glioma treatment. GSCs play important roles in the establishment and recurrence of glioma. Non-stem glioma cells are capable to reprogram to GSCs under the influence of crucial stem genes. Directly targeting GSCs by different strategies will be efficient to gradually eliminate tumor in combination with conventional therapies.

Figure 2

Immunosuppressive cellular components in glioma microenvironment. Tumor cells release molecules which contribute to multiple unique immunosuppression mediated by various cellular players in glioma microenvironment. (A) Cytokines or chemoattractants secreted by glioma cells induce peripheral-derived TAMs and resident microglia to possess M2 phenotype, which enables the production of tumor-promoting factors. (B) Tumor cells induce massive infiltration of MDSCs via multiple approaches, which further exert an immunosuppressive function mainly through T cell inhibition. (C) After recruited to the tumor site, Tregs directly suppress the activity of cytolytic T cells and induce their apoptosis. (D) Despite well-characterized specialties in recognizing and killing tumor cells, the functions of NK cells in glioma microenvironment are limited due to the existence of HLA-G or TGF-β. TAMs, MDSCs and Tregs also collaborate to suppress the activity of NK cells. (E) Tumor-associated neutrophils (TANs) are attracted into tumor bed, where they could evade apoptosis by interacting with diverse molecules, and further benefit the inner-tumor angiogenesis and T cell suppression. (F) In glioma microenvironment, PIGF and ADAM10 cooperate to induce suppressive CD19⁺CD25^hi Bregs, which are responsible for Tregs proliferation and suppression of other T cells.

Figure 3

Hypoxia and immune checkpoint in glioma microenvironment. In immunosuppressive glioma microenvironment, despite the direct molecular and cellular mechanisms, the environmental factors, such as hypoxia and immune checkpoint, also play critical roles in the failure of immunosurveillance. (A) Compared with normal tissues, inner-glioma environment is always recognized as hypoxic and sufficient in immune cell infiltrations, due to the abnormalities in blood vessel morphology and impairing of BBB integrity. Upregulation of hypoxia-related factors, such as HIF-1α, cooperate with specific immune cells from leaky BBB to establish an immunosuppressive microenvironment and suppress the function of cytolytic T cells. (B) Under physiological condition, T cells can be activated through the engagement of MHC to TCR, together with the co-stimulatory signals, to recognize and lyse tumor cells. However, in glioma microenvironment, the elevated expression of CTLA-4 in immunosuppressive cells act as a competitive antagonist of the secondary activation signal, and further lead to the silencing of T cells. Furthermore, induced high expression of PD-1 on T cell surface, as well as PD-L1 on suppressive cells and tumor cells, lead to the anergy and apoptosis of T cells through ligand binding.

Figure 4

Novel therapeutic strategies against the immunosuppressive TME of glioma. As multiple factors, like TAMs, microglia, MDSCs, Tregs and immune checkpoint molecules, work together to enhance immunosuppression and progression of glioma, various strategies have been generated to target these processes. The blockade of suppressive cell recruitment and migration, impairment of their activities, or direct depletion of these factors will synergistically promote the anti-tumor immune responses and improve the prognosis of glioma patients.