Toll-Like Receptors as a Therapeutic Target in the Era of Immunotherapies

Abstract

Toll-like receptors (TLRs) are the pattern recognition receptors, which are activated by foreign and host molecules in order to initiate the immune response. They play a crucial role in the regulation of innate immunity, and several studies have shown their importance in bacterial, viral, and fungal infections, autoimmune diseases, and cancers. The consensus view from an immunological perspective is that TLR agonists can serve either as a possible therapeutic agent or as a vaccine adjuvant toward cancers or infectious diseases and that TLR inhibitors may be a promising approach to the treatment of autoimmune diseases, some cancers, bacterial, and viral infections. These notions are based on the fact that TLR agonists stimulate the secretion of proinflammatory cytokines and in general, the development of proinflammatory responses. Some of the TLR-based inhibitory agents have shown to be efficacious in preclinical models and have now entered clinical trials. Therefore, TLRs seem to hold the potential to serve as a perfect target in the era of immunotherapies. We offer a perspective on TLR-based therapeutics that sheds light on their usefulness and on combination therapies. We also highlight various therapeutics that are in the discovery phase or in clinical trials.

Keywords: SARS-CoV-2; TLR-based immunotherapies; Toll-like receptor; autoimmune disorder; cancer; infection.

FIGURE 1

The Toll-like receptor (TLR) signaling pathway. TLRs are categorized into two groups depending upon whether they utilize a MyD88-dependent pathway or a TRIF-dependent pathway. TLRs 1,2, and 5–9 transmit signals through a MyD88-dependent pathway, whereas TLR3 signaling is mediated by a MyD88-independent pathway. By contrast, TLR4 can signal through MyD88-dependent and MyD88-independent pathways. In case of MyD88-dependent signaling, IL-1R-associated kinases 1/4 (IRAK1/4) recruit TNF receptor–associated factor 6 (TRAF6). TRAF6 can also stimulate interferon signaling by recruitment of IRFs. TRAF6 activates TAK1 which activates two distinct pathways, one of which leads to the activation of the IKK complex-NF-κB pathway and the other to the activation of the mitogen activated protein kinases (MAPKs). The catalytic subunits IKKα, IKKβ, and IKKγ make up the IKK complex. IKKβ is also activated by TAK1. The IKK complex phosphorylates the NF-κB inhibitory protein IκBα, which is then degraded by the proteasome, allowing NF-κB to enter the nucleus. TAK1 activation triggers the activation of MAPK family members leads to the activation of transcription factors such cyclic AMP-responsive element-binding protein (CREB), and activator protein 1 (AP-1). CREB, AP-1 and NF-κB then stimulate proinflammatory mediators and interferons. However, in case of TRIF-dependent signaling, IRF3 and IRF7 are recruited which lead to secretion of type 1 and type 3 interferon.

FIGURE 2

Toll-like receptor (TLR) triggering SARS-CoV-2 infection. SARS-CoV-2, in addition to its main receptor ACE-2, can enter the cell through interaction with TLRs. Currently, TLR4 antagonists including resveratrol, curcumin, quercetin, and berberine are in clinical trials. Pul-042 is a TLR2/6/9 agonist, which stimulates T-helper cells mediated cytokine and interferon secretion. To control a cytokine storm, anakinra, emapalumab, and ruxolitinib are being tested, which are monoclonal antibodies against IL-1β, IFN-γ, and TNF-α. Against IL-6, tocilizumab and sarilumab can be used. M5049, a TLR7/8 antagonist, is currently being tested in clinical trials against COVID.

FIGURE 3

Roles of TLRs in rheumatoid arthritis (RA). Role of TLR2/4 has been extensively studied in RA. Engagement of a TLR by a DAMP promotes release of certain cytokines through MyD88 dependent pathway. Level of TNF-α, IL-6, and IL-1β have been found to be upregulated in RA patients. Upregulated cytokines lead to infiltration of immune cells, proliferation of synoviocytes ultimately leading to bone damage and cartilage degradation. Multiple monoclonal antibodies against TNF-α including etanercept, infliximab and adalimumab are commonly used for RA management. Patients who do not respond to anti-TNF-α antibodies are treated with anti–IL-1β antibodies. TAK-242, which is a TLR4 inhibitor, is also being tested against RA.