Toll-like receptor agonists and RT combinations – an untapped opportunity to induce anti-cancer immunity and improve tumor control

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Abstract

The premise that therapies targeting immune checkpoints may enhance radiation therapy (RT)-induced anti-tumour immunity is being rigorously explored in the pre-clinical setting, and early clinical trials testing this hypothesis are beginning to report.

Whilst such approaches may prove efficacious in certain settings, it is likely that many tumor types, particularly those which have a deeply immune suppressed microenvironment, with little or no T cell infiltration, may require alternative approaches. Thus, there is now considerable drive to develop novel immune modulatory therapies which target other areas of the cancer immunity cycle. Toll-like receptors (TLR) are expressed on sentinel immune cells and play a key role in the host defence against invading pathogens. Innate sensing via TLR-mediated detection of pathogen derived molecular patterns can lead to maturation of antigen-presenting cells and downstream activation of adaptive immunity. After demonstrating promising efficacy in pre-clinical studies, drugs which stimulate TLR have been approved for use clinically, albeit to a limited extent.

There is now a growing body of pre-clinical evidence that novel agonists targeting TLR3, TLR7/8, or TLR9 may lead to enhanced anti-tumor immunity in combination with RT. Mechanistic studies have revealed that TLR agonists enhance dendritic cell-mediated T-cell priming after RT, in some cases leading to the generation of systemic anti-tumour immunity and immune memory.

Here, we describe results from pre-clinical studies which advocate the strategy of combining RT with TLR agonists, discuss reported mechanisms of action, and explore the exciting opportunities of how this approach may be successfully translated into clinical practice.

Bibliographical metadata

Original languageEnglish
JournalInternational Journal of Radiation: Oncology - Biology - Physics
Early online date24 Apr 2020
DOIs
Publication statusPublished - 2020