The Microenvironmental Landscape of Brain Tumors

Abstract

The brain tumor microenvironment (TME) is emerging as a critical regulator of cancer progression in primary and metastatic brain malignancies. The unique properties of this organ require a specific framework for designing TME-targeted interventions. Here, we discuss a number of these distinct features, including brain-resident cell types, the blood-brain barrier, and various aspects of the immune-suppressive environment. We also highlight recent advances in therapeutically targeting the brain TME in cancer. By developing a comprehensive understanding of the complex and interconnected microenvironmental landscape of brain malignancies we will greatly expand the range of therapeutic strategies available to target these deadly diseases.

Keywords: blood-brain barrier; brain metastasis; brain tumor microenvironment; glioma; immunotherapy; tumor-associated macrophage.

Copyright © 2017 Elsevier Inc. All rights reserved.

Figures

Figure 1. Cellular components of the brain tumor microenvironment

Brain tumors are composed of diverse cellular players, ranging from peripherally-derived immune cells to various specialized organ-resident cell types. Each of these cell types contributes to brain tumor biology in unique ways. (A) Tumor-associated macrophages and microglia (TAMs) arise from two distinct sources, including the periphery (bone marrow-derived macrophages; BMDM; CD49d+) or the yolk sac (microglia; MG; CD49d−). TAMs engage in significant bidirectional cross-talk with tumor cells (TC) in the brain, whereby brain tumor cells release cytokines and chemoattractants to recruit TAMs to the microenvironment, and TAMs in turn supply pro-tumorigenic, pro-survival factors. One of the therapeutic strategies used to target TAMs is via CSF-1R inhibitors, including BLZ945 and PLX3397. (B) The potent antigen-presenting ability of dendritic cells is being harnessed clinically for brain tumors, in the form of vaccines (e.g. DCVax-L). Dendritic cells can present tumor antigen to T cells to elicit an anti-tumor immune response. These responses can be further enhanced by factors that are released into the microenvironment by tumor cells, such as reactive oxygen species (ROS) or danger-associated molecular patterns (DAMPs). (C) Neutrophils have prognostic value for brain cancers. In the circulation, a high neutrophil count (i.e. neutrophilia) is associated with positive response to anti-VEGF-A therapy (bevacizumab). However, neutrophilia within tumor tissue in the brain is associated with development of drug resistance to bevacizumab, and high-grade glioma. This suggests there may be tissue-specific reprogramming of neutrophils following their extravasation into tissues. Furthermore, neutrophils can play a role during brain metastasis, where they may seed the pre-metastatic niche in response to S100 inflammatory proteins, to assist in tumor cell colonization. (D) During effector phases of anti-tumor immunity, T lymphocytes are further reprogrammed by the brain microenvironment to extend their retention. This can occur via changes in integrin expression, for example through induction of CD103. T regulatory (T reg) cells can also suppress cytotoxic T cells, leading to an immunosuppressive microenvironment that is permissive to tumor outgrowth. T cells can be activated via multiple immune checkpoint inhibitors, such as those targeting CTLA-4 (e.g. ipilimumab) or PD-1 (e.g. nivolumab, pembrolizumab). (E) Astrocytes are unique to the central nervous system and play important roles in mediating tissue-specific communication in the brain, including in brain tumors. For example, several studies have demonstrated in both primary gliomas and in brain metastases that astrocytes form functional gap junctions with tumor cells, which serve as a physical conduit for transferring signaling molecules in a heterotypic manner. Efforts to disrupt this communication axis pharmacologically have been made, for example with macitentan (an endothelin receptor antagonist) or meclofenamate (a cyclooxygenase inhibitor that modulates gap junctions).

Figure 2. Vascular and lymphatic vessels in the brain

(A) The blood-brain barrier (BBB) serves to protect the brain from inflammation and systemic insults. It is composed of endothelial cells, pericytes, and astrocytes, which tightly seal the endothelium to regulate permeability. Microglia and neurons can additionally contribute to regulation of BBB integrity. Breakdown of junctional integrity can increase permissiveness to seeding of brain-metastatic cancer cells. (B) Recent studies have led to the discovery of lymphatic vasculature in the brain along the dural sinuses in mouse. These vessels exchange fluid with the cerebral spinal fluid (CSF) that surrounds the brain parenchyma, explaining longstanding questions about how immune cells are trafficked into and out of the brain. (C) Brain tumors, particularly gliomas, exhibit extremely high vascularity and angiogenesis. Furthermore, the perivascular niche (PVN) serves as a reservoir for tumor-initiating cells within the brain, which supports tumor outgrowth and aggressive behavior. As such, disrupting the brain vasculature and/or the PVN is of interest for clinical management of brain tumors.