Systematic Review on Tumor Microenvironment in Glial Neoplasm: From Understanding Pathogenesis to Future Therapeutic Perspectives

Abstract

Despite the multidisciplinary management in the treatment of glioblastomas, the average survival of GBM patients is still 15 months. In recent years, molecular biomarkers have gained more and more importance both in the diagnosis and therapy of glial tumors. At the same time, it has become clear that non neoplastic cells, which constitute about 30% of glioma mass, dramatically influence tumor growth, spread, and recurrence. This is the main reason why, in recent years, scientific research has been focused on understanding the function and the composition of tumor microenvironment and its role in gliomagenesis and recurrence. The aim of this review is to summarize the most recent discovery about resident microglia, tumor-associated macrophages, lymphocytes, and the role of extracellular vesicles and their bijective interaction with glioma cells. Moreover, we reported the most recent updates about new therapeutic strategies targeting immune system receptors and soluble factors. Understanding how glioma cells interact with non-neoplastic cells in tumor microenvironment is an essential step to comprehend mechanisms at the base of disease progression and to find new therapeutic strategies for GBM patients. However, no significant results have yet been obtained in studies targeting single molecules/pathways; considering the complex microenvironment, it is likely that only by using multiple therapeutic agents acting on multiple molecular targets can significant results be achieved.

WITHDRAWN: Upregulated HMGB3 resulting in the poor prognosis of lung adenocarcinoma by activating stromal angiogenesis through immune microenvironment

“…Compared to LUAD patients with metastasis or recurrence, early diagnosis and treatment usually result in a prosperous prognosis. A superior biomarker supplies precise guidance and potential value for malignant tumor processing [34]. Through using comprehensive bioinformatics analysis on expression pro le and clinical prognosis, our research revealed that HMGB3 had signi cant diagnostic and therapeutic value on LUAD.…”

Nucleotide‐Binding Oligomerization Domain (NOD)-Like Receptor Subfamily C (NLRC) as a Prognostic Biomarker for Glioblastoma Multiforme Linked to Tumor Microenvironment: A Bioinformatics, Immunohistochemistry, and Machine Learning-Based Study

“…The tumor microenvironment, which comprises ostensibly normal cells (except heterogeneous cancer cells), including stromal and immune cells, is presumed to be genetically stable and less affected by tumor heterogeneity and has a crucial impact on GBM subtype, recurrence, drug resistance, and, subsequently, the survival of patients; 18 it is acknowledged that these nontumoral cells drastically impact tumor development and progression. 4 Thus, the most promising potential for a therapeutic breakthrough lies in pathways targeting the tumor microenvironment of GBM, since therapeutic regimens that target gliomagenesis pathways are inhibited due to the heterogeneity of the tumor. 3 Moreover, we performed further analyses of the potential mechanisms to investigate the functions of NOD1 in the GBM microenvironment.…”

“…Tumor-associated microglia and macrophages, covering the largest proportion of infiltrating immune cells, are associated with more aggressive phenotypes of GBM. 4 In contrast, NK cells recognize target cells and directly lyse tumor cells but cover the lowest part of all GBM immune infiltrations. 34 The ESTIMATE algorithm revealed a positive link between stromal/immune infiltrations and NOD1 expression.…”

“… 5 Furthermore, nontumoral cells, which comprise 30% of the glioma mass and tumor microenvironment, drastically impact tumor development and progression. 4 Therefore, additional biomarkers that are associated with tumoral and nontumoral cells need to be identified to further understand the mechanism and improve the prognosis of GBM.…”

Integration of single-cell RNA sequencing and spatial transcriptomics to reveal the glioblastoma heterogeneity

“…19,20 Glioma-associated microglia and macrophages (GAM) are the most abundant population of immune cells, constituting up to 30% of the tumor mass. [21][22][23] Despite the high content of glioma-associated microglia and macrophages (GAM), GBM is considered immunologically "cold" due to relatively poor infiltration of activated T cells and anergic state of those present in TME. 24 Moreover, the broad range of cell-to-cell interactions between cancer cells and components of the TME affects the biological status of the tumor with an increase in its evasion capacity and resistance to treatment.…”