Abstract
Simple SummaryMacrophages are a specialized immune cell type found in both invertebrates and vertebrates. Versatile in functionality, macrophages carry out important tasks such as cleaning cellular debris in healthy tissues and mounting immune responses during infection. In many cancer types, macrophages make up a significant portion of tumor tissue, and these are aptly called tumor-associated macrophages. In gliomas, a group of primary brain tumors, these macrophages are found in very high frequency. Tumor-associated macrophages can promote glioma development and influence the outcome of various therapeutic regimens. At the same time, these cells provide various potential points of intervention for therapeutic approaches in glioma patients. The significance of tumor-associated macrophages in the glioma microenvironment and potential therapeutic targets are the focus of this review.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.
Highlights
GBM is one of the most common primary brain tumors
MRNA expression profiling demonstrated that a mixed M1/M2 profile in the tumor core was associated with increased overall survival [36]. Another recent study observed that a higher portion of microglia in the tumor-associated macrophages (TAMs) population significantly correlated with increased patient survival, indicating that monocyte-derived TAMs may have stronger tumor promoting properties compared to microglia [110]
Rao et al demonstrated that the anti-PD-1 monoclonal antibody was able to cross the blood–brain barrier (BBB) efficiently, where it reduced the number of PD-1+ microglia
Summary
GBM is one of the most common primary brain tumors. The incidence rate of GBM ranges from 0.59 to 5 per 100,000 [1], which increases dramatically after the age of 54 years [2]. According to the recently published WHO classification, only the IDH-wildtype GBMs are designated as GBM, while the former IDH-mutated GBM lesions are classified as IDH-mutated astrocytoma as they develop from lower grade IDH-mutated astrocytomas [6]. Both entities are diagnosed as WHO grade 4 tumors. Previous studies showed a positive correlation between the abundance of TAMs and glioma grade and a negative correlation with survival [9,10] Immunotherapies such as immune checkpoint inhibitors and CAR T cells are effective for a subset of hematological malignancies but have not shown efficacy in GBM and other solid tumors [11]. We will focus on the potential points of intervention to therapeutically target TAMs in GBM patients
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