Metabolic Remodeling in Glioma Immune Microenvironment: Intercellular Interactions Distinct From Peripheral Tumors

Abstract

During metabolic reprogramming, glioma cells and their initiating cells efficiently utilized carbohydrates, lipids and amino acids in the hypoxic lesions, which not only ensured sufficient energy for rapid growth and improved the migration to normal brain tissues, but also altered the role of immune cells in tumor microenvironment. Glioma cells secreted interferential metabolites or depriving nutrients to injure the tumor recognition, phagocytosis and lysis of glioma-associated microglia/macrophages (GAMs), cytotoxic T lymphocytes, natural killer cells and dendritic cells, promoted the expansion and infiltration of immunosuppressive regulatory T cells and myeloid-derived suppressor cells, and conferred immune silencing phenotypes on GAMs and dendritic cells. The overexpressed metabolic enzymes also increased the secretion of chemokines to attract neutrophils, regulatory T cells, GAMs, and dendritic cells, while weakening the recruitment of cytotoxic T lymphocytes and natural killer cells, which activated anti-inflammatory and tolerant mechanisms and hindered anti-tumor responses. Therefore, brain-targeted metabolic therapy may improve glioma immunity. This review will clarify the metabolic properties of glioma cells and their interactions with tumor microenvironment immunity, and discuss the application strategies of metabolic therapy in glioma immune silence and escape.

Keywords: glioma; immune escape; metabolic reprogramming; metabolic therapy; tumor microenvironment.

FIGURE 1

The breakage of blood brain barrier and the infiltration of immune cells into glioma. (A) Under physiological conditions, the blood brain barrier consists of a firm multilayer barrier. Cerebral vascular endothelial cells form a tight junction structure, which is closely connected with pericytes, and is supported by basement membrane underneath. Astrocytes wrap the basement membrane through the end foot, and microglia maintain the integrity of the barrier. The immune cells originally present in the brain are mainly microglia and dendritic cells (DCs). Peripheral immune cells cannot penetrate the blood brain barrier, and brain tissues do not release recruitment signals to the cerebral blood vessels. (B) Rapid growth of glioma cells not only overexcites neurons to induce seizures, but also injures blood brain barrier. Glioma cells release chemokines and other cytokines through the cracks of blood brain barrier to induce the differentiation, expansion and recruitment of peripheral immune cells, including monocytes (in blood)/macrophages (differentiated from monocytes in brain tissue), cytotoxic T lymphocytes (CTLs), regulatory T cells (Tregs), natural killer (NK) cells, neutrophils, DCs and myeloid-derived suppressor cells (MDSCs), which infiltrate the lesions with immune cells in situ.

FIGURE 2

The recruitment of immune cells and the formation of immunosuppressive glioma microenvironment. (A) Glioma cells release chemokines to lesion tissues, part of which entered peripheral blood through the pathological blood brain barrier. (B) After the chemokine receptors of peripheral and intracranial immune cells captured their ligands, they drive the cells to migrate upstream where chemokines are released. (C) During the infiltration of inflammatory T cells, anti-inflammatory cells, mainly regulatory T cells (Tregs), are recruited to inhibit the antigen presentation of dendritic cells (DCs) and T cell activation, resulting in impaired immune response. In addition to the activation of anti-inflammatory mechanisms, glioma cells perform complex intercellular interactions with immune cells in tumor microenvironment. Cytotoxic T lymphocytes (CTLs) should recognize tumor antigen HEAT repeat-containing protein 1 (HEATR1) and kill glioma cells with natural killer (NK) cells, and CTLs were activated by mature DCs during the presentation of damage associated molecular patterns (DAMPs) released by glioma cells. Glioma cells inhibited the maturation of DCs. Furthermore, glioma cells secreted cytokines to induce the generation and recruitment of tumorigenic Tregs, myeloid-derived suppressor cells (MDSCs), neutrophils and M2 polarized microglia and macrophages, and inhibit the infiltration and tumor lysis of CTLs and NK cells.

FIGURE 3

Interactions between glioma cell metabolism and immunomicroenvironment. (A) Metabolic reprogramming enables glioma cells to express high levels of substrate transporters and metabolic enzymes to obtain sufficient energy in the harsh conditions of lesion, resulting in the deprivation of nutrient substrates and accumulation of immune-interfering metabolites in the extracellular fluid. Abnormally expressed or mutated metabolic enzymes also affected immune cells by regulating the production of chemokines and other cytokines. The actions of these molecules that enter the tumor microenvironment on immune cells and the influences of immune cells on glioma cells metabolism are presented in part (B–H). The Arabic numerals in the figure link the metabolism of glioma cells (A) with immune cells (B–H).