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.

Keywords: TAM biomarker; glioblastoma; glioma; immune checkpoints; immunotherapy; macrophage; microglia; targeted therapies; tumor-associated macrophages (TAMs).

Figure 1

Targeting TAMs in GBM. Strategies of targeting TAMs can be categorized into three distinct approaches. TAM re-education involves targeting the immune checkpoints that provoke an immunosuppressive M2 phenotype. ICI regimens belong to this category. Depending on the glioma model used, CSF1R-inhibition demonstrates either TAM-reprogramming or depleting capabilities. TAM education activates the pro-inflammatory machineries of myeloid cells that can promote phagocytic activity, antigen presentation and the secretion of an array of immune-activating cytokines. TAM depletion targets the ligands and receptors that are involved in macrophage/monocyte infiltration from the periphery. These approaches are not mutually exclusive in a clinical setting. Particular combinations, which need to be tested more thoroughly in the future, could potentially lead to a better outcome.