Synergy of Topical Toll-like Receptor 7 Agonist with Radiation and Low-Dose Cyclophosphamide in a Mouse Model of Cutaneous Breast Cancer
- 15 December 2012
- journal article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 18 (24), 6668-6678
- https://doi.org/10.1158/1078-0432.ccr-12-0984
Abstract
Purpose: This study tested the hypothesis that topical Toll-like receptor (TLR) 7 agonist imiquimod promotes antitumor 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/wk. In some experiments, local ionizing radiation therapy (RT) was delivered to the tumor in three fractions of 8 Gy, given on consecutive days. Cyclophosphamide was given intraperitoneally (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 with 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 cyclophosphamide 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, showing long-term immunologic memory. Conclusions: Topical imiquimod inhibits tumor growth and synergizes with RT. Addition of cyclophosphamide further increases the therapeutic effect and induces protective immunologic memory, suggesting that this combination is a promising strategy for cutaneous breast cancer metastases. Clin Cancer Res; 18(24); 6668–78. ©2012 AACR.Keywords
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