Role of the TLR signaling pathway in the pathogenesis of glioblastoma multiforme with an emphasis on immunotherapy

Abstract

The most malignant brain tumor, glioblastoma multiforme (GBM), has a high mortality rate. Recently, translational elements in GBM therapy have emerged as novel therapeutic strategies in addition to conventional treatment methods. In this way, Toll-like receptor (TLR), PI3K/Akt/mTOR, MAPK/ERK, NOTCH, and other signaling pathways have recently become some of the main signaling pathways in brain tumors. The immunological reactions to brain tumors are mediated by these mechanisms. A family of proteins known as TLRs is essential to the natural defense mechanism because it can identify and react to infections and other danger signals. TLRs have dual functions in the glioma microenvironment including that they can initially activate the innate and adaptive immune responses that support antitumor activity and secondly, their activation can also contribute to tumor progression by promoting inflammation and immune evasion, as they are expressed on both immune cells and tumor cells. TLR agonists are receiving more attention in the treatment of glioma because some of them have demonstrated survival benefits in clinical studies when used in conjunction with immunotherapy, chemotherapy, radiation therapy, and immune checkpoint inhibitors. The most exciting use of TLR agonists is that they can be used as immunomodulators to avoid dose accumulation, boost the efficiency of other therapies, and, by upregulating PD-1, reinforce delayed immune checkpoint resistance against PD-1/PD-L1 inhibition. Therefore, the use of TLR agonists can lead to PD-L1 overexpression, which in turn enhances the efficacy of checkpoint inhibitors and triggers potent anticancer immune responses. In this article, we describe the function of the TLR signaling system, the cellular and molecular elements contributing to the etiology of glioblastoma multiforme, the connection between TLRs and glioma, and their significance for immunotherapy.

Keywords: Immunotherapy; PD-1/PD-L1; TLR signaling pathway; The pathogenesis of glioblastoma.

Graphical abstract

Fig. 1

Overview of the immunotherapy pathways of TLR agonists targeting CNS malignancies. TLR activation triggers the release of cytokines, as well as the death of tumor cells, dendritic cells, macrophages, T cells, and active natural killer (NK) cells. TLR agonists can have two types of effects: systemic (B): These involve boosting the immune system across the body, which improves the body's ability to fight tumors. Systemic effects can cause the body to produce more pro-inflammatory cytokines and activate different immune cells. This helps fight tumors in areas beyond where the treatment was given [80]. and local (A): These are limited to where the TLR agonist is given. Local activation can change the area around a tumor, causing inflammation and the entry of immune cells into the tumor. This targeted approach can make other treatments, such as chemotherapy or radiation, work better by making tumor cells more responsive to them [81].

Fig. 2

Alterations in the glioblastoma tumor microenvironment and their correlation with the peripheral immune system. The immune system of GBM consists of different types of cells, including microglia, special macrophages connected to glioma (GAMs), T cells, and natural killer (NK) cells. These immune cells can make up to half of the tumor size and greatly affect how the immune system fights the tumor. However, factors that weaken the immune system, found in the area around tumors (called the tumor microenvironment), like certain proteins known as IL-10 and TGF-β, create a very strong environment that makes it difficult for the body to fight cancer. This blockade is important for tumor growth and makes immunotherapy harder [97].

Fig. 3

The most widely used glioblastoma immunotherapeutic approaches. (A) Immune checkpoint inhibition mechanism. (B) The development of CAR-T cells and their immediate anti-tumor activities in the context of CAR-T therapy. (C) Tumor-associated antigen peptide vaccination and autologous dendritic cell transfer after exposure to tumor lysate are two distinct vaccination approaches for glioblastoma. (D) Mechanisms of oncolytic viral therapy: from oncolysis to changes in the tumor microenvironment.

Fig. 4

The involvement of signaling pathways, TAMs, TANs, and inflammatory mediators in the tumorigenicity of gliomas. Activation/release is indicated by the color green. Tumor-associated neutrophils (TANs) and macrophages (TAMs) CSF-1,2 and MCP-1,3 are colony-stimulating factors and monocyte chemoattractant proteins, respectively. The cell-derived neurotrophic factor is commonly referred to as GDNF. Various interleukins such as IL-1 α, β, −4, −6, −8, −10, and chemokines like CXCL-1, -12 are involved in immune responses. Additionally, TNF-α, COX-2, prostaglandin E2, PDGF, TGF β, VEGF, MMP-2, 9, IGFBP1, and Bmi-1 represent different signaling molecules and growth factors. Arg-1 denotes arginase-1, NF-κB stands for nuclear factor kappa light chain enhancer of activated B cells, and TLRs refer to toll-like receptors. Furthermore, JAK/STAT denotes Janus kinase-signal transducer and activator of transcription, MAPK represents mitogen-activated protein kinase, and PI3K/Akt/mTOR denotes phosphoinositol-3-kinase-mammalian target of rapamycin.

Fig. 5

APC, T cells, and GBM interact to activate immunological checkpoints that allow the GBM to escape the immune system. The illustration illustrates how miRNA molecules are beginning to exert inhibitory effects on the indicated axis. MiR-138 on T cells interact with PD-1 and CTLA-4, leading to their inhibition. In addition, miR-28 and miR-155 are involved in the suppression of PD-1 and CTLA-4, respectively.