Glioma-Associated Microglia Characterization in the Glioblastoma Microenvironment through a ‘Seed-and Soil’ Approach: A Systematic Review

Abstract

Ever since the discovery of tumor-associated immune cells, there has been growing interest in the understanding of the mechanisms underlying the crosstalk between these cells and tumor cells. A “seed and soil” approach has been recently introduced to describe the glioblastoma (GBM) landscape: tumor microenvironments act as fertile “soil” and interact with the “seed” (glial and stem cells compartment). In the following article, we provide a systematic review of the current evidence pertaining to the characterization of glioma-associated macrophages and microglia (GAMs) and microglia and macrophage cells in the glioma tumor microenvironment (TME). Methods: An online literature search was launched on PubMed Medline and Scopus using the following research string: “((Glioma associated macrophages OR GAM OR Microglia) AND (glioblastoma tumor microenvironment OR TME))”. The last search for articles pertinent to the topic was conducted in February 2022. Results: The search of the literature yielded a total of 349 results. A total of 235 studies were found to be relevant to our research question and were assessed for eligibility. Upon a full-text review, 58 articles were included in the review. The reviewed papers were further divided into three categories based on their focus: (1) Microglia maintenance of immunological homeostasis and protection against autoimmunity; (2) Microglia crosstalk with dedifferentiated and stem-like glioblastoma cells; (3) Microglia migratory behavior and its activation pattern. Conclusions: Aggressive growth, inevitable recurrence, and scarce response to immunotherapies are driving the necessity to focus on the GBM TME from a different perspective to possibly disentangle its role as a fertile ‘soil’ for tumor progression and identify within it feasible therapeutic targets. Against this background, our systematic review confirmed microglia to play a paramount role in promoting GBM progression and relapse after treatments. The correct and extensive understanding of microglia–glioma crosstalk could help in understanding the physiopathology of this complex disease, possibly opening scenarios for improvement of treatments.

Review of Current Human Genome-Scale Metabolic Models for Brain Cancer and Neurodegenerative Diseases

“…Besides neurons and astrocytes that play a central role in gliomas, other glial cell types, oligodendrocytes and microglia, were described to play a role in tumour progression [ 43 ]. Oligodendrocytes are cells engulfing the neuron axon with the myelin sheath to maintain neuronal signal [ 44 ].…”

Glioma-associated microglia/macrophages (GAMs) in glioblastoma: Immune function in the tumor microenvironment and implications for immunotherapy

“…The immune-escape mechanism of GBM relies on two main factors: the intrinsic characteristics of neoplastic cells and the immunosuppressive TME mediated by GAMs. Glioma cells are difficult to identify by the immune due to their downregulation of human leukocyte antigen (HLA) molecules that cover the surface specific tumor antigen molecules ( 95 ). However, the immunosuppressive TME has been recognized as a more significant contributor to promoting tumor immune evasion, facilitating its growth, invasion, and recurrence ( 78 , 79 ).…”

“…GSCs interact with various components in TME to maintain their drug resistance and tumorigenicity. They are located in specific niches where they are protected from therapy exposure and niche-specific factors ( 95 , 115 , 116 ). GAMs mainly accumulate in perivascular and perinecrotic hypoxic niches, where they initiate interactions with SGCs to affect glioma prognosis ( 74 , 95 ).…”

“…They are located in specific niches where they are protected from therapy exposure and niche-specific factors ( 95 , 115 , 116 ). GAMs mainly accumulate in perivascular and perinecrotic hypoxic niches, where they initiate interactions with SGCs to affect glioma prognosis ( 74 , 95 ). GSCs secrete chemokines (such as VEGF, CCL2, CCL5, and CCL7), to recruit GAMs to tumor mass and induce M2 type polarization of GAMs, aiding their transformation and proliferation by building a tumorigenic TME.…”

Editorial: Frontiers in Neuro Oncology and Neurosurgery

“…Menna et al, instead, investigated the mechanisms of crosstalk in the tumoral microenvironment and, with their systematic review, confirmed that microglia play a paramount role in promoting GBM progression and relapse after treatment. This systematic review describes this complex issue by exploring every detail [ 11 ].…”