Radiotherapy and Toll-Like Receptor Agonists

The clinical successes of CTLA4 and PD-1 immune checkpoint blockade in aggressive malignancies such as metastatic melanoma and non-small cell lung carcinoma inaugurate a new era in oncology. Indeed, as opposed to tumor-targeted therapies, it is now clear that immune-targeted therapies designed to enhance the antitumor immune response are a relevant strategy to obtain long-term tumor responses. Interestingly, the study of tumor cell death biology has recently revealed that part of radiotherapy efficacy relies on its ability to trigger an immune response against tumor cells. This “immunogenic cell death” partly relies on the generation of damage-associated molecular patterns, which can stimulate immune sensors such as toll-like receptors. Tumor radiation therapy can therefore be envisioned as a strategy to perform an in situ immunization because it can initiate the release of tumor-associated antigens, deplete immune suppressors, and stimulate antigen-presenting cells via endogenous release of toll-like receptor agonists. Moreover, combinations of radiotherapy with immune checkpoint antibodies are synergistic in preclinical models. The translation of these observations in the clinic is ongoing in early phase I/II trials.