Crosstalk Between Tumor-Associated Microglia/Macrophages and CD8-Positive T Cells Plays a Key Role in Glioblastoma

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.

The ‘Danse Macabre’—Neutrophils the Interactive Partner Affecting Oral Cancer Outcomes

“…Arising from a common progenitor lineage, the multi-layered roles of TANs and TAMs are implicated in almost every step of tumor growth and metastasis. Both TAMs and TANs use multiple overlapping pathways to crosstalk with T cells, including engagement of immune checkpoints and secretion of cytokines, resulting in tumor immune escape, as well as angiogenesis and invasion ( 189 , 190 ). It is known that activated neutrophils provide signals for the activation, maturation, and recruitment of monocytes/macrophages, NK cells, and DCs by releasing IL-8, TNF-α, macrophage inflammatory protein-1α (MIP-1α), and MIP-1β, indicating that neutrophils play a central role in the involvement of these three major cell phenotypes in immunity ( 191 – 194 ).…”

Tumor-Associated Macrophages in Gliomas—Basic Insights and Treatment Opportunities

“…perforin, granzyme A, granzyme B, Fas ligand and IFN-γ [ 88 ]. Another prominent molecule expressed by TAMs that can compromise T cell functionality is Arginase 1, which can curb T cell activation and proliferation by depleting the essential amino acid arginine [ 89 , 90 ]. Recently, the aryl hydrocarbon receptor (AHR) was also implicated in the process of TAM-directed modulation of T cell immunity [ 91 ].…”

The Role of Metabolic Plasticity of Tumor-Associated Macrophages in Shaping the Tumor Microenvironment Immunity

“…TAM-secreted TGF-beta and IL-10 hinder the maturation of the dendritic cells (DCs), promote the expansion of regulatory T cells (Tregs), and suppress the activity of T cells and NK cells [ 50 , 51 , 52 , 53 ]. Additionally, TAMs express PD-L1, PD-L2, and PD-1, as well as the CTL-associated protein 4 (CTLA-4) ligands CD80 and CD86, which bind to their receptors in the CD8 + T cells and lead to the inhibition of the T cells’ cytotoxic function [ 54 ]. Additionally, TAM-secreted TGF-β inhibits the expression of perforin, granzyme A and B, IFNγ, and the FAS ligand [ 55 ] or CXCR3 on T cells [ 39 ], which are vital for the T cell-mediated cytotoxicity.…”

“…Additionally, TAM-secreted TGF-β inhibits the expression of perforin, granzyme A and B, IFNγ, and the FAS ligand [ 55 ] or CXCR3 on T cells [ 39 ], which are vital for the T cell-mediated cytotoxicity. TAMs expressing arginase, an arginine metabolizing enzyme, also affect the T cell function by creating an arginine-deprived TME and altering the T cell metabolism [ 54 ] ( Figure 1 ). Therefore, TAM possesses a multifaceted avenue to control the T cells’ function in the TME, which is the center of most immunotherapeutic approaches.…”