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.

Glioblastoma (GB) is the most frequent and aggressive primary brain tumor. It is a highly infiltrating tumor. Complete eradication by surgery is difficult. The probability of survival beyond two years is very low. Magnetic resonance imaging (MRI) is a routine procedure for diagnosing gliomas. However, morphological MRI often fails to identify and quantify the presence of infiltration in peritumoral non-enhanced areas, resulting in inaccuracy in the assessment of invasive margins. Up to 50% of the patients show pseudo-progression. Morphological MRI fails to distinguish the marked enhancement in the tumor bed caused by radionecrosis from actual tumor progression. Diagnosis of GB recurrence through MR morphological sequences has a sensitivity and specificity of about 68% and 77%. Such percentages rise thanks to the use of non-morphological sequences (PWI, DWI, MRS), which are used in routine tumor protocols only in large centers and interpreted by expert neuroradiologists. Biomarkers in conjunction with MRI may help improve the classification, prognosis, and treatment choice. GB is highly infiltrated with monocytic cells, tumor-associated macrophages (TAMs), that invade the peripheral blood. Our group has recently identified a splice isoform of FK506-binding protein 51 (FKBP51) as a reliable TAM marker. We found an expansion in circulating CD163/FKBP51s monocytes in a cohort of GB patients. In patients with an MRI diagnosis of complete surgical tumor removal, these monocytes dramatically decreased. In patients with an MRI diagnosis of residual tumor, most of the peripheral CD163 monocytes that in the preoperative stage were FKBP51s- had turned into FKBP51s+. CD163/FKBP51s+ monocytes helped to distinguish between radionecrosis and actual tumor progression. These results suggest that circulating CD163/FKBP51s+ monocytes are associated with GB and can be helpful in monitoring GB patients. Citation Format: Carolina Giordano, Giuseppe Maria Della Pepa, Simona Romano, Laura Marrone, Carlo Maria Donzelli, Maria Fiammetta Romano, Simona Gaudino. Combined use of MRI and TAM analysis in GB monitoring. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5474.