TLR7 Agonist Imiquimod Improves the Therapeutic Antitumor Effect of High-Dose-Rate Brachytherapy

Brachytherapy (BT) is a local radiation treatment method for solid tumors. A single 10 Gy high-dose-rate (HDR) BT acts as an "in situ" vaccination. Tumor microenvironment (TME)-dependent radio-resistance mechanisms, such as increasing immunosuppression and hypoxia, lead to tumor recurrence after radiotherapy. Our study aimed to determine whether adding imiquimod (IMQ) to anticancer therapy would overcome TME-mediated mechanisms of radiotherapy resistance. IMQ, a toll-like receptor 7 (TLR7) agonist, acts as an immunostimulant and a vascular normalizing agent.

Mice with well-developed tumors were treated with IMQ at a vascular-normalized dose of 50 μg, followed 5 days later by a single 10 Gy HDR BT. The dose coverage was planned using Discovery RT computed tomography CT scans. Irradiation was performed with a high-dose-rate afterloader equipped with an iridium-192 radioactive source.

In mice treated with a combination of IMQ and BT, we observed significant inhibition of melanoma tumor growth. We also noticed an effective therapeutic effect in mice with breast cancer, resulting in significantly prolonged survival and complete tumor regression in 20% of treated mice. In the blood of treated mice, we observed leukopenia with eosinophilia. In tumors, there was enhanced infiltration by cytotoxic CD8⁺ T lymphocytes. The depletion of CD8⁺ T cells completely abolished the effect of the combined therapy.

The combination of IMQ with HDR brachytherapy induces a synergistic effect, improving the therapeutic antitumor effect of brachytherapy. Our data indicate that it is reasonable to use drugs that prevent changes in the TME in combination with radiotherapy.