The role of glutamate receptors in the regulation of the tumor microenvironment

Abstract

Glutamate, as one of the most important carbon sources in the TCA cycle, is central in metabolic processes that will subsequently influence tumor progression. Several factors can affect the expression of glutamate receptors, playing either a tumor-promoting or tumor-suppressor role in cancer. Thus, the activation of glutamate receptors by the ligand could play a role in tumor development as ample studies have demonstrated the expression of glutamate receptors in a broad range of tumor cells. Glutamate and its receptors are involved in the regulation of different immune cells' development and function, as suggested by the receptor expression in immune cells. The activation of glutamate receptors can enhance the effectiveness of the effector's T cells, or decrease the cytokine production in immunosuppressive myeloid-derived suppressor cells, increasing the antitumor immune response. These receptors are essential for the interaction between tumor and immune cells within the tumor microenvironment (TME) and the regulation of antitumor immune responses. Although the role of glutamate in the TCA cycle has been well studied, few studies have deeply investigated the role of glutamate receptors in the regulation of cancer and immune cells within the TME. Here, by a systematic review of the available data, we will critically assess the physiopathological relevance of glutamate receptors in the regulation of cancer and immune cells in the TME and provide some unifying hypotheses for futures research on the role of glutamate receptors in the immune modulation of the tumor.

Keywords: glutamate; glutamate receptors; immunoregulation; metabolic processes; tumor micro-environment.

Figure 1

The role of glutamate in cells. (A) the role of glutamate in protein synthesis. The amino-acid glutamate is the substrate for protein synthesis, important for the maintenance and promotion of cell function. (B) the role of glutamate in the TCA. Extracellular glutamate is one of the most important sources of carbon in The TCA cycle. In the mitochondria, glutamate is deaminated to α-ketoglutarate (α-KG) by glutamate dehydrogenase (GDH), which is incorporated in the TCA cycle for energy production. (C) glutamate and the maintenance of cell homeostasis and regulation of cell proliferation. The amino-acid exchangers also known as cystine-glutamate transporter (xCT/SLC7A11), play a very important role in maintaining redox homeostasis by exchanging extracellular cystine in exchange for intracellular glutamate to maintain intracellular redox and the energy production for the regulation of cell proliferation.

Figure 2

General structure of glutamate receptors. Metabotropic glutamate receptors belong to the family C G-protein-coupled receptors (GPCR). Group I mGluRs is coupled to phospholipase C, while groups II and III are negatively coupled to adenylate cyclase (AC). The iGluRs are ligand-gated cation channels that are divided into three groups: N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), and 2-carboxy-3-carboxymethyl-4-isopropenyl pyrrolidine (kainate, KA) receptors.

Figure 3

Main signaling pathways involved in the regulation of cancer by metabotropic glutamate receptor (mGluR) and inotropic glutamate receptor (iGluR). Group I mGluRs are coupled to phospholipase C (PLC) while groups II and III are coupled to adenylate cyclase (AC). NMDAR are ligand-gated ion channels that mediate a rapid depolarization of the membrane. The binding of glutamate to the glutamate binding site acts as a first messenger and induces the depolarization of the membrane leading to the influx of Ca²⁺ in the intracellular space, followed by the activation of the corresponding signaling pathways. Glutamate is the agonist of AMPAR, and the channel opens when two sites are occupied by glutamate. Within the receptor, the GluN2 subunit plays a critical role in the determination of the Ca²⁺ permeability of the AMPAR. Upon binding of the amino-acid glutamate to its receptors, the intracellular signal transduction mechanisms induce the activation of different signaling pathways leading to cell proliferation and tumor growth.

Figure 4

The role of glutamate in the interaction between neurons, immune cells, and tumor cells. A neuron can release neurotrophic factors and cytokines leading to the regulation of TME. These cytokines can act directly on tumor cells leading to their proliferation and tumor growth. Within the TME, immune cells and tumor cells interact together. Glutamate can bind to glutamate receptors on myeloid and lymphoid cells leading to an increase in the antitumor immune response or the inhibition of the antitumor immune response.

Figure 5

The role of glutamate receptors in immune cells. The activation of mGluR4 on the surface of DCs decreases the production of the protumor IL-23 and decreases tumor growth. mGluR4 also increases the expression of CD80 and CD86. In NK and T cells, the activation of mGluR4 decreases the antitumor immune response by the decrease in NK and T cells infiltration and the decrease in IFN-γ production. In Myeloid-derived suppressor cells (MDSCs), the activation of mGluR2/3 decrease the immune-suppressive properties of MDSCs on T cells and decreases the effects of MDSCs in cancer cells. In macrophages, the activation of mGluR5 increases the level of PPAR-γ and a shift from M1 to M2 phenotype and the decrease in IFN-γ production, while the activation of NMDAR increases the production of TNF-α.