Synergy of topical toll-like receptor 7 agonist with radiation and low-dose cyclophosphamide in a mouse model of cutaneous breast cancer.
Synergy of topical toll-like receptor 7 agonist with radiation and low-dose cyclophosphamide in a mouse model of cutaneous breast cancer.
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DOI：
10.1158/1078-0432.ccr-12-0984
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发表时间：
2012-12-15
期刊：
影响因子：
--
通讯作者：
Demaria S
中科院分区：
文献类型：
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作者：
Dewan MZ;Vanpouille-Box C;Kawashima N;DiNapoli S;Babb JS;Formenti SC;Adams S;Demaria S
这项研究测试了局部应用Toll样受体(TLR)7激动剂咪喹莫特促进抗肿瘤免疫并与其他治疗方法在皮肤受累乳腺癌模型中协同作用的假设。TSA小鼠乳腺癌细胞皮下注射。变成同基因的小鼠。将5%咪喹莫特或安慰剂乳膏外用于肿瘤周围的剃须皮肤，每周三次。在一些实验中，局部电离放射治疗(RT)被给予肿瘤，连续3天给予8Gy3次。环磷酰胺(CY)腹腔注射。一次给药2 mg/只小鼠。对小鼠的肿瘤生长和存活率进行了跟踪。咪喹莫特治疗显著抑制肿瘤生长，这种作用与CD11c+、CD4+和CD8+细胞增加肿瘤浸润有关，并随着CD8+细胞的耗尽而消失。与单一治疗相比，咪喹莫特联合放射治疗显著增强了肿瘤反应(p<；0.005)，11%至66%的受照射肿瘤完全消退。重要的是，外用咪喹莫特也能抑制放射野外的继发性肿瘤的生长。在咪喹莫特和RT治疗开始前给予小剂量环磷酰胺，可进一步改善肿瘤抑制和减少肿瘤复发。保持无肿瘤状态的小鼠拒绝接受TSA细胞的致瘤接种，显示出长期的免疫记忆。外用咪喹莫特抑制肿瘤生长，与RT有协同作用。CY的加入进一步提高了治疗效果，并诱导了保护性免疫记忆，表明这种联合治疗乳腺癌皮肤转移是一种很有前途的策略。
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. 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. 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. 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.