Abstract
Glioblastoma is considered to be the most malignant disease of the central nervous system, and it is often associated with poor survival. The immune microenvironment plays a key role in the development and treatment of glioblastoma. Among the different types of immune cells, tumor-associated microglia/macrophages (TAM/Ms) and CD8-positive (CD8+) T cells are the predominant immune cells, as well as the most active ones. Current studies have suggested that interaction between TAM/Ms and CD8+ T cells have numerous potential targets that will allow them to overcome malignancy in glioblastoma. In this review, we summarize the mechanism and function of TAM/Ms and CD8+ T cells involved in glioblastoma, as well as update on the relationship and crosstalk between these two cell types, to determine whether this association alters the immune status during glioblastoma development and affects optimal treatment. We focus on the molecular factors that are crucial to this interaction, and the role that this crosstalk plays in the biological processes underlying glioblastoma treatment, particularly with regard to immune therapy. We also discuss novel therapeutic targets that can aid in resolving reticular connections between TAM/Ms and CD8+ T cells, including depletion and reprogramming TAM/Ms and novel TAM/Ms-CD8+ T cell cofactors with potential translational usage. In addition, we highlight the challenges and discuss future perspectives of this crosstalk between TAM/Ms and CD8+ T cells.
Highlights
Glioblastoma, known as glioblastoma multiforme (GBM), is one of the most malignant diseases that is thought to originate within the central nervous system (CNS) [1]
On further evaluating the mechanisms underlying IL-12-related CAR-Tboosting effect, IL-12 overexpression in chimeric antigen receptor T cell (CAR-T) cells demonstrated that an increase in the first apoptosis signal ligand (FASL), and an increase in the recognition of the first apoptosis signal (FAS) in macrophages, induces tumorassociated macrophages (TAMs)/M apoptosis and thereby causes depletion of tumorassociated microglia/macrophages (TAM/Ms) [87]. These results suggest that the modification of IL-12 expression can cause TAM/M depletion through the FAS/FASL pathway
The anti-MACRO antibody treatment reduces IL-10 expression, which helps trigger a decline in IL-1b. These cascaded cytokine fluctuations cause the TAM/M phenotype to shift from the immunosuppressive subtype to the immunostimulant subtype, thereby changing the tumor microenvironment to a pro-inflammatory phase and promoting the cytosis effect of CD8+ T cells in immune checkpoint inhibitor therapy
Summary
Glioblastoma, known as glioblastoma multiforme (GBM), is one of the most malignant diseases that is thought to originate within the central nervous system (CNS) [1]. The anti-MACRO antibody treatment reduces IL-10 expression, which helps trigger a decline in IL-1b These cascaded cytokine fluctuations cause the TAM/M phenotype to shift from the immunosuppressive subtype to the immunostimulant subtype, thereby changing the tumor microenvironment to a pro-inflammatory phase and promoting the cytosis effect of CD8+ T cells in immune checkpoint inhibitor therapy. Another study wherein IL-12 was directly injected into mice with lung cancer showed that the IL-12 injection reduced IL-10 and TGF-b levels at the tumor site, which are considered to be signals of the M2 TAM/M phenotype, and increased the expression of IL-6 and TNF-a [96] These studies suggest that TAM/M reprograming helps enhance the anti-tumor effect of CAR-T therapy by altering the immune inhibition environment created by TAM/ Ms (Figure 3B). Targeting TGF-b1 and TGF-b2 may improve intratumoral T cell infiltration and enhance the effectiveness of immunotherapeutic approaches in GBM [111]
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