The strange Microenvironment of Glioblastoma

Glioblastoma (GB) is the most common and deadly primary malignant tumor of the central nervous system (CNS). According to the 2021 WHO classification of tumors of the central nervous system [1], glioblastomas are IDH-wildtype adult-type diffuse gliomas characterized by microvascular proliferation or necrosis or TERT promotor mutation or EGFR gene amplification or +7/–10 chromosome copy number changes.

The 2022 Central Brain Tumor Registry of the United States (CBTRUS) reports that GB was the most common malignant CNS tumor between 2015 and 2019 with an incidence of 3.26 cases per 100,000 habitants, accounting for 14.2% of all CNS tumors and 50.1% of primary malignant brain tumors in the United States (US) [2]. The incidence of GB increases with age and is more common in Caucasian males and in older adults. In the past years, an increase in GB incidence is observed in the US, 57,805 new cases were reported between 2011 and 2015, compared to 63,258 between 2015 and 2019, which is a 9% increase [2], [3]. Also, this trend seems to continue increasing, as the last CBTRUS report estimated 14,190 new GB cases in 2022, a 12.1% increase when compared to the 12,652 annual average new cases from 2019–2022.

Regardless of the clinical protocol consisting of surgical resection, followed by temozolomide (TMZ) chemotherapy and radiotherapy, the 5-year survival rate of GB patients is extremely low, with only 6.9%. The increasing incidence of these tumors, their significant aggressiveness, and the morbidity they generate, make them a real public health issue, justifying the urgent need to develop new approaches to target their progression.

The tumor microenvironment (TME) is composed of the tumor extra cellular matrix and the different cell types that are present in addition to cancer cells (Fig. 1). These include immune cells, endothelial cells, pericytes, fibroblasts, neurons, astrocytes and other tissue resident cells [4]. In the case of brain tumors, the tumor microenvironment is rather distinct because of the presence of the unique brain-resident astrocytic, microglial and neuronal cell types [5].

Among TME components, tumor blood vessels are deeply involved in nutrient and oxygen delivery to prevent the limited diffusion in growing tumors. The multidirectional interplay between blood vessels, cancer cells and other TME components plays an important role in GB progression [6].

In early stages of tumorigenesis, the presence of the blood-brain barrier (BBB) can reduce immune infiltration to the developing tumor and favors its immune escape [7]. The particularly immune-privileged brain microenvironment, with rare physiological infiltration of peripheral immune cells, renders the immune compartment of the TME different from this of other solid tumors [4]: the main cell types infiltrating the GB tumor mass are microglia/macrophages and T cells [8]. Other immune cells like natural killer (NK) cells and dendritic cells (DCs) are almost absent within the brain tumor mass, and microglial cells and macrophages are the predominant antigen presenting cells (APCs) in this context [4], [8], [9]. Moreover, overexpression in gliomas of immunosuppressive pathways in the tumor cell/TME crosstalk, such as TGFβ [10], [11], CD161 [12], adenosine pathway molecules [13], [14], and others participate in this “cold” immune state of GBs.

Recent work has highlighted the role of neurons in GB growth through direct interaction between neurons and tumor cells forming glioma-neuron synapses dependent on activation of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors [15], [16], [17]. This recent works indicate that neuronal input may contribute to the invasion step of tumor expansion and for TMZ resistance.

In this article, we will summarize some recent developments with regard to the TME in GB and focus more specifically on the tumor vasculature and the immune system. For the neuronal compartment readers should refer to recently published state-of-the art articles [5], [17], [18] (Fig. 1).

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