Synergy of topical Toll-Like Receptor 7 agonist with radiation and low dose cyclophosphamide in a mouse model of cutaneous breast cancer
Menée sur un modèle murin de cancer du sein, cette étude évalue l'efficacité antitumorale d'un protocole thérapeutique comportant une faible dose de cyclophosphamide, un traitement topique à base d'un agoniste du récepteur TLR 7 et une radiothérapie
Purpose: This study tested the hypothesis that topical Toll-Like Receptor (TLR) 7 agonist imiquimod promotes anti-tumor immunity and synergizes with other treatments in a model of skin-involving breast cancer. Experimental Design: TSA mouse breast carcinoma cells were injected s.c. into syngeneic mice. Imiquimod 5% or placebo cream was applied topically on the shaved skin overlying tumors three times/week. In some experiments, local ionizing radiation therapy (RT) was delivered to the tumor in 3 fractions of 8 Gy, given on consecutive days. Cyclophosphamide (CY) was given i.p. in one dose of 2 mg/mouse. Mice were followed for tumor growth and survival. Results: Treatment with imiquimod significantly inhibited tumor growth, an effect that was associated with increased tumor infiltration by CD11c+, CD4+ and CD8+ cells, and abolished by depletion of CD8+ cells. Administration of imiquimod in combination with RT enhanced significantly tumor response compared to either treatment alone (p<0.005), and 11 to 66% of irradiated tumors completely regressed. Importantly, the addition of topical imiquimod also resulted in growth inhibition of a secondary tumor outside of the radiation field. Low dose CY given before start of treatment with imiquimod and RT further improved tumor inhibition and reduced tumor recurrence. Mice that remained tumor-free rejected a tumorigenic inoculum of TSA cells, demonstrating long-term immunological memory. Conclusions: Topical imiquimod inhibits tumor growth and synergizes with RT. Addition of CY further increases the therapeutic effect and induces protective immunological memory, suggesting that this combination is a promising strategy for cutaneous breast cancer metastases.