Toll-Like Receptor Agonists and Radiation Therapy Combinations: An Untapped Opportunity to Induce Anticancer Immunity and Improve Tumor control

Abstract

The premise that therapies targeting immune checkpoints can enhance radiation therapy (RT)-induced antitumor immunity is being explored rigorously in the preclinical setting, and early clinical trials testing this hypothesis are beginning to report. Although such approaches might prove efficacious in certain settings, it is likely that many tumor types, particularly those that have a deeply immune-suppressed microenvironment with little or no T cell infiltration, will require alternative approaches. Thus, there is now considerable drive to develop novel immune modulatory therapies that target other areas of the cancer immunity cycle. Toll-like receptors (TLRs) are expressed on sentinel immune cells and play a key role in the host defense 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 preclinical studies, drugs that stimulate TLR have been approved for use clinically, albeit to a limited extent. There is a growing body of preclinical evidence that novel agonists targeting TLR3, TLR7/8, or TLR9 in combination with RT might lead to enhanced antitumor immunity. 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 antitumor immunity and immune memory. In this report, we describe results from preclinical studies that 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.