Application of toll-like receptors (TLRs) and their agonists in cancer vaccines and immunotherapy

Abstract

Toll-like receptors (TLRs) are pattern recognition receptors (PRRs) expressed in various immune cell types and perform multiple purposes and duties involved in the induction of innate and adaptive immunity. Their capability to propagate immunity makes them attractive targets for the expansion of numerous immunotherapeutic approaches targeting cancer. These immunotherapeutic strategies include using TLR ligands/agonists as monotherapy or combined therapeutic strategies. Several TLR agonists have demonstrated significant efficacy in advanced clinical trials. In recent years, multiple reports established the applicability of TLR agonists as adjuvants to chemotherapeutic drugs, radiation, and immunotherapies, including cancer vaccines. Cancer vaccines are a relatively novel approach in the field of cancer immunotherapy and are currently under extensive evaluation for treating different cancers. In the present review, we tried to deliver an inclusive discussion of the significant TLR agonists and discussed their application and challenges to their incorporation into cancer immunotherapy approaches, particularly highlighting the usage of TLR agonists as functional adjuvants to cancer vaccines. Finally, we present the translational potential of rWTC-MBTA vaccination [irradiated whole tumor cells (rWTC) pulsed with phagocytic agonists Mannan-BAM, TLR ligands, and anti-CD40 agonisticAntibody], an autologous cancer vaccine leveraging membrane-bound Mannan-BAM, and the immune-inducing prowess of TLR agonists as a probable immunotherapy in multiple cancer types.

Toll-like receptor signaling in multiple myeloma cells promotes the expression of pro-survival genes B-cell lymphoma 2 and MYC and modulates the expression of B-cell maturation antigen

“…The situation in vivo is however far more complex. TLR agonists have been tested as adjuvants to increase the efficacy of cancer vaccines or cancer treatment ( 54 ). In MM, it was shown that a TLR9 agonist could restore the ability of patient-derived plasmacytoid dendritic cells (pDCs) to stimulate T-cell proliferation and that activating TLR9 in a xenograft MM model reduced tumor load ( 55 ).…”

Colonic Tuft Cells: The Less-Recognized Therapeutic Targets in Inflammatory Bowel Disease and Colorectal Cancer

“…Various immunomodulatory agents, such as toll-like receptor agonists, cytokines, and immune cell modulators, are being investigated in CRC to enhance anti-tumor immune responses [ 191 , 192 ]. These agents may target pathways affected by TC-mediated immunomodulation, promoting a more favorable immune microenvironment for anti-tumor activity.…”

High‐risk HPV oncoproteins E6 and E7 and their interplay with the innate immune response: Uncovering mechanisms of immune evasion and therapeutic prospects

“…This is supported by several ongoing clinical trials assessing the efficacy of combining TLR agonists with chemotherapy, radiotherapy, or various other immunotherapies, also in the context of HPV-associated cancers. [176][177][178] Lastly, their efficacy suggests they could serve as adjuvants for the production of therapeutic HPV vaccines aimed at promoting cellular responses while disrupting the anti-inflammatory microenvironment generated by HPV + cells. 179…”