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

Abstract

Glioma refers to a group of primary brain tumors which includes glioblastoma (GBM), astrocytoma and oligodendroglioma as major entities. Among these, GBM is the most frequent and most malignant one. The highly infiltrative nature of gliomas, and their intrinsic intra- and intertumoral heterogeneity, pose challenges towards developing effective treatments. The glioma microenvironment, in addition, is also thought to play a critical role during tumor development and treatment course. Unlike most other solid tumors, the glioma microenvironment is dominated by macrophages and microglia—collectively known as tumor-associated macrophages (TAMs). TAMs, like their homeostatic counterparts, are plastic in nature and can polarize to either pro-inflammatory or immunosuppressive states. Many lines of evidence suggest that immunosuppressive TAMs dominate the glioma microenvironment, which fosters tumor development, contributes to tumor aggressiveness and recurrence and, very importantly, impedes the therapeutic effect of various treatment regimens. However, through the development of new therapeutic strategies, TAMs can potentially be shifted towards a proinflammatory state which is of great therapeutic interest. In this review, we will discuss various aspects of TAMs in the context of glioma. The focus will be on the basic biology of TAMs in the central nervous system (CNS), potential biomarkers, critical evaluation of model systems for studying TAMs and finally, special attention will be given to the potential targeted therapeutic options that involve the TAM compartment in gliomas.

Identification of the novel prognostic biomarker, MLLT11, reveals its relationship with immune checkpoint markers in glioma

“…Previous studies have found that there were a large number of TAMs in GBM. There is a correlation between TAM density and glioma grade, indicating that TAMs support tumor development (51,52). Interestingly, negative correlations were found in this study between MLLT11 expression and M2 macrophages, as well as M1 macrophages.…”

Novel macrophage-related gene prognostic index for glioblastoma associated with M2 macrophages and T cell dysfunction

“…TAMs are known sources of immune checkpoints in TME, which contributes to the dysfunction of tumor-infiltrating CD8 T cells and frustration of anti-tumor immunity ( 12 , 41 ). We first explored the expression pattern of immune checkpoints between groups.…”

“…Yet, the application of ICI in GBM is limited, which may partially ascribe to the immune-suppressive tumor microenvironment (TME) ( 8 , 9 ). Tumor-associated macrophages (TAMs) in GBM refer to blood-derived monocytes/macrophages and intrinsic microglia, and the alternatively activated TAMs orchestrate an immunosuppressive TME thus impeding the anti-tumor immune activity ( 10 – 12 ). Interstingly, increasing evidence suggests that TAMs involve in the expression of immune checkpoints in the TME and play a vital role in inducing CD8 T lymphocyte dysfunction ( 11 , 13 – 15 ).…”

Bibliometric analysis of research on immunogenic cell death in cancer

“…Indeed, tumor mutational load strongly predicts the response to ICIs in cancer patients ( Schumacher and Schreiber, 2015 ). Cancer cells can downregulate surface antigens to evade recognition by immune system, and release immunosuppressive molecules to inhibit activities of effector immune cells ( Chan et al, 2019 ; Andersen et al, 2022 ).…”