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.

Neoantigen Dendritic Cell Vaccination Combined with Anti-CD38 and CpG Elicits Anti-Tumor Immunity against the Immune Checkpoint Therapy-Resistant Murine Lung Cancer Cell Line LLC1

“…It has been reported that Toll-like receptor (TLR) agonists engender several changes in the tumor environment that increase responsiveness to PD-1 blockade [ 30 ]. TLR9 agonist CpG has been reported to enhance infiltration of CD8 + T cells in the tumor [ 31 ].…”

Innate and Adaptive Responses of Intratumoral Immunotherapy with Endosomal Toll-Like Receptor Agonists

“…Overall, TLR stimulation in cancer cells has been mainly associated to protumoral activity, while TLR stimulation in immune cells preferentially leads to the activation of innate and adaptive antitumoral and proinflammatory responses in the TME (Figure 2). In the TME, TLRs can be expressed by multiple immune cells, including monocytes, macrophages, dendritic cells, B cells, T cells, mast cells, and natural killer (NK) cells, as well as by non-immune cells, such as epithelial cells, fibroblasts, and cancer cells [36]. Contrary to cancer cells, TLR signaling in immune cells has mainly been associated with antitumor effects controlled by their immunostimulation and maturation, ultimately leading to cytokine secretion.…”

Viral-Host Dependency Factors as Therapeutic Targets to Overcome Antiviral Drug-Resistance: A Focus on Innate Immune Modulation

“…TLRs located in intracellular endosomal compartments recognize nucleic acids characteristic of virus and bacteria such as dsRNA (TLR3), ssRNA (TLR7/8) and unmethylated DNA with CpG motifs (TLR9) (109). TLR structure and signaling transduction are widely described elsewhere (68,(110)(111)(112).…”

“…The modulation of TLR7/8 pathway is another interesting mechanism to be considered. Imiquimod (brand name Aldara ™ ) is FDA-approved TLR7/8a (mainly a TLR7a) that is currently in use for the treatment of HPV-and HSV-induced genital and perianal warts (111). In vitro antiviral activity of Imiquimod against HIV-1 has also been reported in pretreated human macrophages in a mechanism involving the downregulation of HIV entry coreceptors CCR5 and CD4 (123).…”

“…Authors suggest that interaction with TLR4 would enhance ACE2 expression to facilitate viral entry (135,136). Although all these studies remain to be confirmed, the role and modulation of TLR2 and TLR4 pathways in the context of SARS-Cov-2 should be explored as potential therapeutic intervention (68,111,134).…”